15-74411925-C-T

Position:

chr15-74411925-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_003612.5(SEMA7A):c.1382G>A(p.Arg461His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R461C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SEMA7A
NM_003612.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.576

Variant links:

Genes affected

SEMA7A (HGNC:10741): (semaphorin 7A (JohnMiltonHagen blood group)) This gene encodes a member of the semaphorin family of proteins. The encoded preproprotein is proteolytically processed to generate the mature glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein. The encoded protein is found on activated lymphocytes and erythrocytes and may be involved in immunomodulatory and neuronal processes. The encoded protein carries the John Milton Hagen (JMH) blood group antigens. Mutations in this gene may be associated with reduced bone mineral density (BMD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

SEMA7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05952972).

BP6

Variant 15-74411925-C-T is Benign according to our data. Variant chr15-74411925-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2392590.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SEMA7A	NM_003612.5 linkuse as main transcript	c.1382G>A	p.Arg461His	missense_variant	11/14	ENST00000261918.9
SEMA7A	NM_001146029.3 linkuse as main transcript	c.1340G>A	p.Arg447His	missense_variant	10/13
SEMA7A	NM_001146030.3 linkuse as main transcript	c.887G>A	p.Arg296His	missense_variant	11/14
SEMA7A	XM_047433177.1 linkuse as main transcript	c.1259G>A	p.Arg420His	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9 linkuse as main transcript	c.1382G>A	p.Arg461His	missense_variant	11/14	1	NM_003612.5	P1	O75326-1
SEMA7A	ENST00000543145.6 linkuse as main transcript	c.1340G>A	p.Arg447His	missense_variant	10/13	2			O75326-2
SEMA7A	ENST00000542748.6 linkuse as main transcript	c.887G>A	p.Arg296His	missense_variant	11/14	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251194

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.062

T;T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.28

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.013

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.19

MVP

0.45

MPC

0.57

ClinPred

0.036

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.31

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