15-74410681-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003612.5(SEMA7A):c.1944C>T(p.Ala648=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 1,609,660 control chromosomes in the GnomAD database, including 7,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2533 hom., cov: 32)
  • Exomes 𝑓: 0.064 (5041 hom.)
• Consequence: SEMA7A NM_003612.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.95

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-74410681-G-A is Benign according to our data. Variant chr15-74410681-G-A is described in ClinVar as [Benign]. Clinvar id is 3059310.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA7A	NM_003612.5	c.1944C>T	p.Ala648=	synonymous_variant	14/14	ENST00000261918.9
SEMA7A	NM_001146029.3	c.1902C>T	p.Ala634=	synonymous_variant	13/13
SEMA7A	NM_001146030.3	c.1449C>T	p.Ala483=	synonymous_variant	14/14
SEMA7A	XM_047433177.1	c.1821C>T	p.Ala607=	synonymous_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1944C>T	p.Ala648=	synonymous_variant	14/14	1	NM_003612.5	P1
SEMA7A	ENST00000543145.6	c.1902C>T	p.Ala634=	synonymous_variant	13/13	2
SEMA7A	ENST00000542748.6	c.1449C>T	p.Ala483=	synonymous_variant	14/14	5

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20537 AN: 152164 Hom.: 2530 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0787

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.0846 AC: 21106 AN: 249526 Hom.: 1775 AF XY: 0.0826 AC XY: 11155 AN XY: 134970

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0334

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0637 AC: 92778 AN: 1457378 Hom.: 5041 Cov.: 32 AF XY: 0.0643 AC XY: 46556 AN XY: 724140

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.0338

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0699

Gnomad4 NFE exome AF: 0.0487

Gnomad4 OTH exome AF: 0.0772

GnomAD4 genome AF: 0.135 AC: 20564 AN: 152282 Hom.: 2533 Cov.: 32 AF XY: 0.135 AC XY: 10051 AN XY: 74466

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.0593

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0787

Gnomad4 NFE AF: 0.0484

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0661 Hom.: 817

Bravo AF: 0.141

Asia WGS AF: 0.140 AC: 485 AN: 3478

EpiCase AF: 0.0471

EpiControl AF: 0.0457

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA7A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.79
Dann	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs2075592; hg19: chr15-74703022; COSMIC: COSV56090930; COSMIC: COSV56090930;