rs373822999

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001372044.2(SHANK3):c.2398G>A(p.Ala800Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,564,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.19

Publications

1 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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.2398G>A	p.Ala800Thr	missense	Exon 22 of 25	NP_001358973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHANK3	ENST00000692848.2		c.2395G>A	p.Ala799Thr	missense	Exon 20 of 23	ENSP00000510794.2
SHANK3	ENST00000262795.8	TSL:5	c.1813G>A	p.Ala605Thr	missense	Exon 18 of 21	ENSP00000489147.3
SHANK3	ENST00000664402.3		c.355G>A	p.Ala119Thr	missense	Exon 3 of 6	ENSP00000499475.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

168594

AF XY:

0.0000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000991

AC:

AN:

1412378

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

698152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32104

American (AMR)

AF:

0.00

AC:

AN:

37210

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25310

East Asian (EAS)

AF:

0.0000546

AC:

AN:

36636

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5366

European-Non Finnish (NFE)

AF:

0.00000920

AC:

AN:

1087440

Other (OTH)

AF:

0.00

AC:

AN:

58558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 01, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.050

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.43

PhyloP100

9.2

PrimateAI

Pathogenic

0.81

REVEL

Benign

0.19

Sift4G

Uncertain

0.015

Vest4

0.57

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.60

Mutation Taster

=57/43

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over