Genetic Variant SH2D4B:p.Asp300Glu (chr10-80609463-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001388272.1(SH2D4B):c.900T>A(p.Asp300Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,990 control chromosomes in the GnomAD database, including 23,937 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1990 hom., cov: 31)

Exomes 𝑓: 0.17 ( 21947 hom. )

Consequence

SH2D4B
NM_001388272.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.00

Publications

15 publications found

Variant links:

Genes affected

SH2D4B (HGNC:31440): (SH2 domain containing 4B) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SH2D4B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003282398).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4B	NM_001388272.1 link	c.900T>A	p.Asp300Glu	missense_variant	Exon 6 of 8	ENST00000646907.2	NP_001375201.1
SH2D4B	NM_207372.2 link	c.897T>A	p.Asp299Glu	missense_variant	Exon 6 of 7		NP_997255.2	Q5SQS7-2
SH2D4B	NM_001145719.1 link	c.753T>A	p.Asp251Glu	missense_variant	Exon 6 of 7		NP_001139191.1	Q5SQS7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH2D4B	ENST00000646907.2 link	c.900T>A	p.Asp300Glu	missense_variant	Exon 6 of 8		NM_001388272.1	ENSP00000494732.1	A0A2R8Y5Q0
SH2D4B	ENST00000339284.6 link	c.897T>A	p.Asp299Glu	missense_variant	Exon 6 of 7	2		ENSP00000345295.2	Q5SQS7-2
SH2D4B	ENST00000313455.5 link	c.753T>A	p.Asp251Glu	missense_variant	Exon 6 of 7	2		ENSP00000314242.4	Q5SQS7-3
SH2D4B	ENST00000372150.7 link	n.242T>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21554

AN:

152056

Hom.:

1992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.145

GnomAD2 exomes

AF:

0.172

AC:

43286

AN:

251404

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.0444

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.175

Gnomad EAS exome

AF:

0.369

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.170

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.167

AC:

243889

AN:

1461816

Hom.:

21947

Cov.:

AF XY:

0.166

AC XY:

120431

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0445

AC:

1491

AN:

33480

American (AMR)

AF:

0.158

AC:

7054

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

4613

AN:

26134

East Asian (EAS)

AF:

0.398

AC:

15802

AN:

39700

South Asian (SAS)

AF:

0.117

AC:

10069

AN:

86254

European-Finnish (FIN)

AF:

0.192

AC:

10239

AN:

53418

Middle Eastern (MID)

AF:

0.164

AC:

948

AN:

5766

European-Non Finnish (NFE)

AF:

0.165

AC:

183562

AN:

1111956

Other (OTH)

AF:

0.167

AC:

10111

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

11340

22680

34019

45359

56699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6528

13056

19584

26112

32640

<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:

0.142

AC:

21543

AN:

152174

Hom.:

1990

Cov.:

AF XY:

0.145

AC XY:

10798

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0476

AC:

1978

AN:

41540

American (AMR)

AF:

0.146

AC:

2227

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

625

AN:

3472

East Asian (EAS)

AF:

0.384

AC:

1979

AN:

5156

South Asian (SAS)

AF:

0.116

AC:

561

AN:

4822

European-Finnish (FIN)

AF:

0.205

AC:

2171

AN:

10582

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.169

AC:

11460

AN:

67986

Other (OTH)

AF:

0.144

AC:

305

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

921

1842

2762

3683

4604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.172

Hom.:

1754

Bravo

AF:

0.136

TwinsUK

AF:

0.171

AC:

634

ALSPAC

AF:

0.153

AC:

589

ESP6500AA

AF:

0.0533

AC:

235

ESP6500EA

AF:

0.170

AC:

1463

ExAC

AF:

0.169

AC:

20519

Asia WGS

AF:

0.222

AC:

771

AN:

3478

EpiCase

AF:

0.170

EpiControl

AF:

0.171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.7

(source)

DANN

Benign

0.74

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.66

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.5

N;.;N

REVEL

Benign

0.014

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;.;T

Polyphen

0.0010

B;.;B

Vest4

0.023

MPC

0.14

ClinPred

0.00077

GERP RS

-6.9

gMVP

0.11

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over