rs61729471

Positions:

chr22-50714943-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001372044.2(SHANK3):c.2347G>A(p.Ala783Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,593,368 control chromosomes in the GnomAD database, including 1,114 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1041 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020890832).

BP6

Variant 22-50714943-G-A is Benign according to our data. Variant chr22-50714943-G-A is described in ClinVar as [Benign]. Clinvar id is 167676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50714943-G-A is described in Lovd as [Likely_benign]. Variant chr22-50714943-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2 linkuse as main transcript	c.2347G>A	p.Ala783Thr	missense_variant	22/25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
SHANK3	ENST00000262795.7 linkuse as main transcript	c.1762G>A	p.Ala588Thr	missense_variant	18/22	5	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000445220.7 linkuse as main transcript	c.814G>A	p.Ala272Thr	missense_variant	9/13	5		A0A0U1RR93
SHANK3	ENST00000664402.2 linkuse as main transcript	c.304G>A	p.Ala102Thr	missense_variant	3/7		ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4120

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00587

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0336

AC:

7063

AN:

210022

Hom.:

174

AF XY:

0.0354

AC XY:

4039

AN XY:

114142

show subpopulations

Gnomad AFR exome

AF:

0.00604

Gnomad AMR exome

AF:

0.0309

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.000770

Gnomad SAS exome

AF:

0.0729

Gnomad FIN exome

AF:

0.0399

Gnomad NFE exome

AF:

0.0325

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0343

AC:

49366

AN:

1441130

Hom.:

1041

Cov.:

AF XY:

0.0353

AC XY:

25233

AN XY:

715096

show subpopulations

Gnomad4 AFR exome

AF:

0.00513

Gnomad4 AMR exome

AF:

0.0309

Gnomad4 ASJ exome

AF:

0.0264

Gnomad4 EAS exome

AF:

0.000465

Gnomad4 SAS exome

AF:

0.0715

Gnomad4 FIN exome

AF:

0.0416

Gnomad4 NFE exome

AF:

0.0338

Gnomad4 OTH exome

AF:

0.0308

GnomAD4 genome

AF:

0.0270

AC:

4117

AN:

152238

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2054

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00585

Gnomad4 AMR

AF:

0.0306

Gnomad4 ASJ

AF:

0.0308

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0758

Gnomad4 FIN

AF:

0.0380

Gnomad4 NFE

AF:

0.0351

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0312

Hom.:

109

Bravo

AF:

0.0236

TwinsUK

AF:

0.0356

AC:

132

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00717

AC:

ESP6500EA

AF:

0.0323

AC:

274

ExAC

AF:

0.0293

AC:

3510

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2018	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

.;T

Eigen

Benign

0.027

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.65

REVEL

Benign

0.10

Sift4G

Uncertain

0.032

D;D

Vest4

0.49

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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