Variant chr22-50721504-T-TG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001372044.2(SHANK3):c.3865dupG(p.Ala1289fs) 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. 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

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 links:

SHANK3 (HGNC:):

SHANK3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 208759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2 linkuse as main transcript	c.3865dupG	p.Ala1289fs	frameshift_variant	24/25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
SHANK3	ENST00000262795.7 linkuse as main transcript	c.3280dupG	p.Ala1094fs	frameshift_variant	20/22	5	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000445220.7 linkuse as main transcript	c.2332dupG	p.Ala778fs	frameshift_variant	11/13	5		A0A0U1RR93
SHANK3	ENST00000664402.2 linkuse as main transcript	c.1822dupG	p.Ala608fs	frameshift_variant	5/7		ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151636

Hom.:

Cov.:

FAILED QC

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

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1410908

Hom.:

Cov.:

AF XY:

0.0000244

AC XY:

AN XY:

697262

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000543

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00000644

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phelan-McDermid syndrome

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 24, 2023	Criteria applied: PVS1,PS2,PS3,PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 09, 2023	PVS1, PS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	PVS1, PS2, PS3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Aug 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Oct 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 17, 2019	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SHANK3: PVS1, PS2:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2022	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

Pathogenic, criteria provided, single submitter	research	Liping Wei Laboratory, Peking University	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

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. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This has been reported to be a recurrent mutation in individuals with autism spectrum disorder and 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 01, 2022

- -

Neurodevelopmental disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 14, 2020

- -

SHANK3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over