22-50721504-TGGG-TGGGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001372044.2(SHANK3):c.3865dupG(p.Ala1289GlyfsTer69) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,410,908 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SHANK3
NM_001372044.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: -0.292

Publications

5 publications found

Variant links:

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 Gene-Disease associations (from GenCC):

Phelan-McDermid syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
schizophrenia 15
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SHANK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 22-50721504-T-TG is Pathogenic according to our data. Variant chr22-50721504-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 208759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.3865dupG	p.Ala1289GlyfsTer69	frameshift_variant	Exon 24 of 25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2 link	c.3862dupG	p.Ala1288GlyfsTer69	frameshift_variant	Exon 22 of 23			ENSP00000510794.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151636

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000994

AC:

AN:

160994

AF XY:

0.0000691

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000789

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000127

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1410908

Hom.:

Cov.:

AF XY:

0.0000244

AC XY:

AN XY:

697262

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32234

American (AMR)

AF:

0.0000543

AC:

AN:

36808

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25324

East Asian (EAS)

AF:

0.00

AC:

AN:

36730

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80706

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

48708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000644

AC:

AN:

1086380

Other (OTH)

AF:

0.00

AC:

AN:

58476

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74162

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67834

Other (OTH)

AF:

0.00

AC:

AN:

2108

Alfa

AF:

0.000254

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phelan-McDermid syndrome

Pathogenic:9

Jul 03, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PS2_VSTR,PS4

Feb 07, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 03, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 17, 2019

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SHANK3 c.3679dupG p.(Ala1227GlyTer56) variant, also referred to as p.(Ala1214GlyTer69), p.(Ala1227Glyfs), or p.(Ala1243GlyfsTer69), causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with a phenotype consistent with Phelan-McDermid syndrome (Durand et al. 2007; O'Roak et al. 2014; De Rubeis et al. 2018; Zhou et al. 2019). De novo inheritance was confirmed in four of the cases as well as germline mosaicism in a sibling pair who inherited the variant from the mother. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Ala1227 residue lies in exon 21, which has been shown to be a hotspot for de novo variants resulting in loss of function (De Rubeis et al. 2018). The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.3679dupG p.(Ala1227GlyTer56) variant is classified as pathogenic for Phelan-McDermid syndrome.

Jan 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 09, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS2

Aug 14, 2020

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 06, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS2, PS3, PP5

not provided

Pathogenic:3

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHANK3: PVS1, PS2:Moderate

Jan 14, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in two male siblings with autism with presumed germline mosaicism in their mother (Durand et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32050889, 33256793, 21565394, 21606927, 23100419, 25356970, 17173049, 29719671, 30763456, 34737294, 33619735)

Autism spectrum disorder

Pathogenic:2

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2018

Liping Wei Laboratory, Peking University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Inborn genetic diseases

Pathogenic:1

Apr 23, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3679dupG (p.A1227Gfs*69) alteration, located in exon 21 (coding exon 21) of the SHANK3 gene, consists of a duplication of G at position 3679, causing a translational frameshift with a predicted alternate stop codon after 69 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.01% (16/160994) total alleles studied; however, this variant was flagged as a low confidence call. This has been reported to be a recurrent variant in individuals with features consistent with Phelan-McDermid syndrome, often occurring de novo (Durand, 2007; De Rubeis, 2018; Loureiro, 2021). Based on the available evidence, this alteration is classified as pathogenic.

Phelan-McDermid syndrome;C3151380:Schizophrenia 15

Pathogenic:1

Feb 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neurodevelopmental disorder

Pathogenic:1

Sep 14, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHANK3-related disorder

Pathogenic:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SHANK3 c.3679dupG variant is predicted to result in a frameshift and premature protein termination (p.Ala1227Glyfs*69). This variant has been reported in many individuals with Phelan-McDermid syndrome or autism spectrum disorder. The variant was reported de novo in several of these individuals and inherited from mosaic parents in others (see, for example, Durand et al. 2007. PubMed ID: 17173049; De Rubeis et al. 2018. PubMed ID: 29719671; Loureiro et al. 2021. PubMed ID: 34737294). In vitro and in vivo experimental studies suggest this variant impacts protein function (referred to as Shank3^STOP, Durand et al. 2012. PubMed ID: 21606927; referred to as InsG, Arons et al. 2012. PubMed ID: 23100419; referred to as InsG3680, Zhou et al. 2016. PubMed ID: 26687841). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SHANK3 are expected to be pathogenic. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.29

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over