Genetic Variant SHD:p.Gly13Asp (chr19-4280101-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020209.4(SHD):c.38G>A(p.Gly13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHD
NM_020209.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65

Publications

0 publications found

Variant links:

Genes affected

SHD (HGNC:30633): (Src homology 2 domain containing transforming protein D) Predicted to enable phosphotyrosine residue binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SHD links:

ENSG00000303295 (HGNC:):

ENSG00000303295 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21225598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHD	NM_020209.4 link	c.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 6	ENST00000543264.7	NP_064594.3	Q96IW2
SHD	NM_001372011.1 link	c.38G>A	p.Gly13Asp	missense_variant	Exon 2 of 7		NP_001358940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHD	ENST00000543264.7 link	c.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 6	1	NM_020209.4	ENSP00000446058.1	Q96IW2
SHD	ENST00000599689.1 link	c.38G>A	p.Gly13Asp	missense_variant	Exon 1 of 5	5		ENSP00000470181.1	M0QYZ4
ENSG00000303295	ENST00000793432.1 link	n.176+65C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459994

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111382

Other (OTH)

AF:

0.00

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.38G>A (p.G13D) alteration is located in exon 1 (coding exon 1) of the SHD gene. This alteration results from a G to A substitution at nucleotide position 38, causing the glycine (G) at amino acid position 13 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

0.022

Eigen_PC

Benign

0.085

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

2.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.047

Sift

Benign

0.062

T;.

Sift4G

Benign

0.34

T;T

Polyphen

0.61

P;.

Vest4

0.18

MutPred

0.14

Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);

MVP

0.64

MPC

0.60

ClinPred

0.95

GERP RS

3.3

Varity_R

0.17

gMVP

0.17

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over