Genetic Variant SH2D4B:p.Lys135Glu (chr10-80571486-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001388272.1(SH2D4B):c.403A>G(p.Lys135Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SH2D4B
NM_001388272.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.01

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25794804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4B	NM_001388272.1 link	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 8	ENST00000646907.2	NP_001375201.1
SH2D4B	NM_207372.2 link	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 7		NP_997255.2	Q5SQS7-2
SH2D4B	NM_001145719.1 link	c.256A>G	p.Lys86Glu	missense_variant	Exon 3 of 7		NP_001139191.1	Q5SQS7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH2D4B	ENST00000646907.2 link	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 8		NM_001388272.1	ENSP00000494732.1	A0A2R8Y5Q0
SH2D4B	ENST00000339284.6 link	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 7	2		ENSP00000345295.2	Q5SQS7-2
SH2D4B	ENST00000313455.5 link	c.256A>G	p.Lys86Glu	missense_variant	Exon 3 of 7	2		ENSP00000314242.4	Q5SQS7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403A>G (p.K135E) alteration is located in exon 3 (coding exon 3) of the SH2D4B gene. This alteration results from a A to G substitution at nucleotide position 403, causing the lysine (K) at amino acid position 135 to be replaced by a glutamic acid (E). 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

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0099

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.48

N;.;N

REVEL

Benign

0.14

Sift

Benign

0.46

T;.;T

Sift4G

Benign

0.76

T;.;T

Polyphen

0.99

D;.;P

Vest4

0.44

MutPred

0.28

Loss of MoRF binding (P = 0.0399);Loss of MoRF binding (P = 0.0399);.;

MVP

0.59

MPC

0.67

ClinPred

0.92

GERP RS

5.6

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over