chr22-50720741-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001372044.2(SHANK3):c.3094G>T(p.Ala1032Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,230,590 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 3 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017478019).

BP6

Variant 22-50720741-G-T is Benign according to our data. Variant chr22-50720741-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}. Variant chr22-50720741-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000517 (76/146882) while in subpopulation NFE AF= 0.00102 (67/65984). AF 95% confidence interval is 0.000819. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.3094G>T	p.Ala1032Ser	missense_variant	Exon 24 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
SHANK3	ENST00000262795.7 link	c.2509G>T	p.Ala837Ser	missense_variant	Exon 20 of 22	5	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000445220.7 link	c.1561G>T	p.Ala521Ser	missense_variant	Exon 11 of 13	5		A0A0U1RR93
SHANK3	ENST00000664402.2 link	c.1051G>T	p.Ala351Ser	missense_variant	Exon 5 of 7		ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes

AF:

0.000518

AC:

AN:

146788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000550

AC:

AN:

52690

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

31632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000806

AC:

874

AN:

1083708

Hom.:

Cov.:

AF XY:

0.000760

AC XY:

404

AN XY:

531676

show subpopulations

Gnomad4 AFR exome

AF:

0.0000517

Gnomad4 AMR exome

AF:

0.000147

Gnomad4 ASJ exome

AF:

0.000145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000164

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.000913

Gnomad4 OTH exome

AF:

0.000871

GnomAD4 genome

AF:

0.000517

AC:

AN:

146882

Hom.:

Cov.:

AF XY:

0.000461

AC XY:

AN XY:

71544

show subpopulations

Gnomad4 AFR

AF:

0.000146

Gnomad4 AMR

AF:

0.000135

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000118

Gnomad4 NFE

AF:

0.00102

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000476

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHANK3: BS1 -

Nov 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17999366) -

not specified

Uncertain:1

Nov 06, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Phelan-McDermid syndrome;C3151380:Schizophrenia 15

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 06, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SHANK3-related disorder

Benign:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0053

.;T

Eigen

Benign

0.052

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.68

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.79

PrimateAI

Pathogenic

0.92

REVEL

Benign

0.21

Sift4G

Benign

0.56

T;T

Vest4

0.091

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.075

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