15-74411642-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_003612.5(SEMA7A):c.1491C>T(p.Gly497=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,612,364 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: SEMA7A NM_003612.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.48

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=-0.83).
• BP6: Variant 15-74411642-G-A is Benign according to our data. Variant chr15-74411642-G-A is described in ClinVar as [Benign]. Clinvar id is 3042116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00641 (976/152250) while in subpopulation AFR AF= 0.0221 (920/41544). AF 95% confidence interval is 0.021. There are 10 homozygotes in gnomad4. There are 481 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA7A	NM_003612.5	c.1491C>T	p.Gly497=	synonymous_variant	12/14	ENST00000261918.9
SEMA7A	NM_001146029.3	c.1449C>T	p.Gly483=	synonymous_variant	11/13
SEMA7A	NM_001146030.3	c.996C>T	p.Gly332=	synonymous_variant	12/14
SEMA7A	XM_047433177.1	c.1368C>T	p.Gly456=	synonymous_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1491C>T	p.Gly497=	synonymous_variant	12/14	1	NM_003612.5	P1
SEMA7A	ENST00000543145.6	c.1449C>T	p.Gly483=	synonymous_variant	11/13	2
SEMA7A	ENST00000542748.6	c.996C>T	p.Gly332=	synonymous_variant	12/14	5
SEMA7A	ENST00000569617.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152132 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00155 AC: 385 AN: 248786 Hom.: 0 AF XY: 0.00113 AC XY: 152 AN XY: 134614

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.000992

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000658 AC: 961 AN: 1460114 Hom.: 11 Cov.: 33 AF XY: 0.000566 AC XY: 411 AN XY: 726314

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00641 AC: 976 AN: 152250 Hom.: 10 Cov.: 32 AF XY: 0.00646 AC XY: 481 AN XY: 74428

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00361 Hom.: 0

Bravo AF: 0.00779

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Aug 20, 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	-0.83
Cadd	Benign	3.8
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150179930; hg19: chr15-74703983; COSMIC: COSV56090368; COSMIC: COSV56090368;