15-74411588-T-C

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.1545A>G(p.Gln515=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,588,012 control chromosomes in the GnomAD database, including 83,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (14129 hom., cov: 32)
  • Exomes 𝑓: 0.29 (69657 hom.)
• Consequence: SEMA7A NM_003612.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37

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=-0.91).
• BP6: Variant 15-74411588-T-C is Benign according to our data. Variant chr15-74411588-T-C is described in ClinVar as [Benign]. Clinvar id is 3060979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA7A	NM_003612.5	c.1545A>G	p.Gln515=	synonymous_variant	12/14	ENST00000261918.9
SEMA7A	NM_001146029.3	c.1503A>G	p.Gln501=	synonymous_variant	11/13
SEMA7A	NM_001146030.3	c.1050A>G	p.Gln350=	synonymous_variant	12/14
SEMA7A	XM_047433177.1	c.1422A>G	p.Gln474=	synonymous_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1545A>G	p.Gln515=	synonymous_variant	12/14	1	NM_003612.5	P1
SEMA7A	ENST00000543145.6	c.1503A>G	p.Gln501=	synonymous_variant	11/13	2
SEMA7A	ENST00000542748.6	c.1050A>G	p.Gln350=	synonymous_variant	12/14	5
SEMA7A	ENST00000569617.1	n.52A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59446 AN: 151898 Hom.: 14084 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.347 AC: 80691 AN: 232822 Hom.: 16352 AF XY: 0.346 AC XY: 43488 AN XY: 125586

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.556

Gnomad SAS exome AF: 0.525

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.295 AC: 422985 AN: 1435996 Hom.: 69657 Cov.: 36 AF XY: 0.299 AC XY: 213087 AN XY: 711824

Gnomad4 AFR exome AF: 0.674

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.516

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.392 AC: 59562 AN: 152016 Hom.: 14129 Cov.: 32 AF XY: 0.393 AC XY: 29212 AN XY: 74304

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.546

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.357

Alfa AF: 0.275 Hom.: 10570

Bravo AF: 0.406

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 17, 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	-0.91
Cadd	Benign	8.9
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs741761; hg19: chr15-74703929; COSMIC: COSV56091520; COSMIC: COSV56091520;