Genetic Variant NM_001103161.2:c.749A>G (chr1-20724133-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001103161.2(SH2D5):c.749A>G(p.Tyr250Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SH2D5
NM_001103161.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Publications

1 publications found

Variant links:

Genes affected

SH2D5 (HGNC:28819): (SH2 domain containing 5) Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

SH2D5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103161.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D5	NM_001103161.2	MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 7 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.497A>G	p.Tyr166Cys	missense	Exon 6 of 9	NP_001096630.1	Q6ZV89-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D5	ENST00000444387.7	TSL:2 MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 7 of 10	ENSP00000406026.2	Q6ZV89-1
SH2D5	ENST00000870131.1		c.749A>G	p.Tyr250Cys	missense	Exon 8 of 11	ENSP00000540190.1
SH2D5	ENST00000870132.1		c.749A>G	p.Tyr250Cys	missense	Exon 8 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000808

AC:

AN:

247486

AF XY:

0.00000743

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460608

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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.:

Alfa

AF:

0.0000605

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0078

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.2

PhyloP100

4.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MVP

0.57

MPC

0.58

ClinPred

0.92

GERP RS

4.9

Varity_R

0.55

gMVP

0.72

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over