dbSNP rs530255181: SHANK3:p.Ala1031Thr (chr22-50720741-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000692848.2(SHANK3):c.3091G>A(p.Ala1031Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,230,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1031S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

SHANK3
ENST00000692848.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.23

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Phelan-McDermid syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
schizophrenia 15
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SHANK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17448592).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.3094G>A	p.Ala1032Thr	missense_variant	Exon 24 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2 link	c.3091G>A	p.Ala1031Thr	missense_variant	Exon 22 of 23			ENSP00000510794.2		A0A8I5KZC4

Frequencies

GnomAD3 genomes

AF:

0.00000681

AC:

AN:

146788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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

GnomAD2 exomes

AF:

0.0000380

AC:

AN:

52690

AF XY:

0.0000632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000461

AC:

AN:

1083712

Hom.:

Cov.:

AF XY:

0.00000752

AC XY:

AN XY:

531678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19356

American (AMR)

AF:

0.00

AC:

AN:

13608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13836

East Asian (EAS)

AF:

0.00

AC:

AN:

11314

South Asian (SAS)

AF:

0.0000820

AC:

AN:

60958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

902356

Other (OTH)

AF:

0.00

AC:

AN:

39054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000681

AC:

AN:

146788

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71438

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

40932

American (AMR)

AF:

0.00

AC:

AN:

14782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65994

Other (OTH)

AF:

0.00

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

.;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.44

PhyloP100

2.2

PrimateAI

Pathogenic

0.93

REVEL

Benign

0.24

Sift4G

Benign

0.44

T;T

Vest4

0.22

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.12

Mutation Taster

=53/47

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over