rs73892912

Positions:

chr22-50704769-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001372044.2(SHANK3):c.1989G>A(p.Thr663Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,609,424 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

SHANK3
NM_001372044.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.05

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 22-50704769-G-A is Benign according to our data. Variant chr22-50704769-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50704769-G-A is described in Lovd as [Likely_benign]. Variant chr22-50704769-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00328 (499/152280) while in subpopulation AFR AF= 0.0112 (466/41546). AF 95% confidence interval is 0.0104. There are 1 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2 linkuse as main transcript	c.1989G>A	p.Thr663Thr	synonymous_variant	18/25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
SHANK3	ENST00000262795.7 linkuse as main transcript	c.1404G>A	p.Thr468Thr	synonymous_variant	14/22	5	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000445220.7 linkuse as main transcript	c.456G>A	p.Thr152Thr	synonymous_variant	5/13	5		A0A0U1RR93
SHANK3	ENST00000414786.7 linkuse as main transcript	n.1988G>A		non_coding_transcript_exon_variant	15/23	5
SHANK3	ENST00000673971.2 linkuse as main transcript	n.1761G>A		non_coding_transcript_exon_variant	15/23		ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

500

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000221

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000923

AC:

220

AN:

238406

Hom.:

AF XY:

0.000646

AC XY:

AN XY:

130026

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.000565

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.000687

GnomAD4 exome

AF:

0.000578

AC:

842

AN:

1457144

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

404

AN XY:

724518

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.000748

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000819

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000329

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00328

AC:

499

AN:

152280

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00381

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SHANK3: BP4, BP7, BS1 -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 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

-0.63

CADD

Benign

4.6

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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