NM_001372044.2:c.3218G>T

Variant names:

• chr22-50720865-G-T
• rs767058690
• NM_001372044.2:c.3218G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001372044.2(SHANK3):​c.3218G>T​(p.Gly1073Val) variant causes a missense change. The variant allele was found at a frequency of 0.000827 in 1,374,150 control chromosomes in the GnomAD database, including 1 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.26

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007617742).
• BP6: Variant 22-50720865-G-T is Benign according to our data. Variant chr22-50720865-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587798.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr22-50720865-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0006 (90/149918) while in subpopulation NFE AF= 0.00109 (73/67214). AF 95% confidence interval is 0.000886. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.3218G>T	p.Gly1073Val	missense_variant	Exon 24 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.2633G>T	p.Gly878Val	missense_variant	Exon 20 of 22	5		ENSP00000489147.3
SHANK3	ENST00000445220.7	c.1685G>T	p.Gly562Val	missense_variant	Exon 11 of 13	5
SHANK3	ENST00000664402.2	c.1175G>T	p.Gly392Val	missense_variant	Exon 5 of 7			ENSP00000499475.2

Frequencies

GnomAD3 genomes AF: 0.000601 AC: 90 AN: 149810 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000598

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000412

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000976

GnomAD3 exomes AF: 0.00105 AC: 24 AN: 22808 Hom.: 0 AF XY: 0.00103 AC XY: 14 AN XY: 13592

Gnomad AFR exome AF: 0.00287

Gnomad AMR exome AF: 0.000253

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000250

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00269

GnomAD4 exome AF: 0.000855 AC: 1047 AN: 1224232 Hom.: 1 Cov.: 34 AF XY: 0.000843 AC XY: 502 AN XY: 595206

Gnomad4 AFR exome AF: 0.000254

Gnomad4 AMR exome AF: 0.000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000703

Gnomad4 FIN exome AF: 0.000333

Gnomad4 NFE exome AF: 0.000977

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000600 AC: 90 AN: 149918 Hom.: 0 Cov.: 33 AF XY: 0.000533 AC XY: 39 AN XY: 73188

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.000597

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000412

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000965

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.000525

ExAC AF: 0.000336 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHANK3: BS1 -

Mar 02, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25188300, 20385823, 28371232) -

not specified Uncertain:1

Nov 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SHANK3 c.3257G>T (p.Arg1086Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 127098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3257G>T in individuals affected with Phelan-McDermid Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Benign:1

Dec 07, 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

May 22, 2022

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	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Uncertain	-0.14	T
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.28
Sift4G	Benign	0.12	T;T
Vest4		0.34
GERP RS		3.0
gMVP		0.19

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

Other links and lift over

dbSNP: rs767058690; hg19: chr22-51159293;