Variant 9-37955998-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003028.3(SHB):c.1111C>T(p.Arg371Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,592,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 1 hom. )

Consequence

SHB
NM_003028.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Variant links:

Genes affected

SHB (HGNC:10838): (SH2 domain containing adaptor protein B) Enables phosphotyrosine residue binding activity. Predicted to be involved in several processes, including angiogenesis; apoptotic process; and signal transduction. Predicted to act upstream of or within several processes, including hematopoietic stem cell proliferation; negative regulation of oocyte maturation; and positive regulation of immune response. Located in cytoplasmic ribonucleoprotein granule; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.352099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHB	NM_003028.3 linkuse as main transcript	c.1111C>T	p.Arg371Trp	missense_variant	4/6	ENST00000377707.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHB	ENST00000377707.4 linkuse as main transcript	c.1111C>T	p.Arg371Trp	missense_variant	4/6	1	NM_003028.3	P1	Q15464-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

209486

Hom.:

AF XY:

0.0000798

AC XY:

AN XY:

112758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000417

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000322

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000278

AC:

AN:

1440334

Hom.:

Cov.:

AF XY:

0.0000350

AC XY:

AN XY:

714298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000242

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000907

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000189

ExAC

AF:

0.0000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.1111C>T (p.R371W) alteration is located in exon 4 (coding exon 4) of the SHB gene. This alteration results from a C to T substitution at nucleotide position 1111, causing the arginine (R) at amino acid position 371 to be replaced by a tryptophan (W). 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

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.019

MetaRNN

Benign

0.35

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Uncertain

0.029

Sift4G

Uncertain

0.057

Polyphen

1.0

Vest4

0.59

MutPred

0.30

Loss of loop (P = 0.1258);

MVP

0.28

MPC

0.81

ClinPred

0.24

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.64

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