15-74414831-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003612.5(SEMA7A):c.1095+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,614,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (8 hom.)
• Consequence: SEMA7A NM_003612.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001696
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-74414831-C-T is Benign according to our data. Variant chr15-74414831-C-T is described in ClinVar as [Benign]. Clinvar id is 3033564.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA7A	NM_003612.5	c.1095+7G>A		splice_region_variant, intron_variant		ENST00000261918.9
SEMA7A	NM_001146029.3	c.1053+7G>A		splice_region_variant, intron_variant
SEMA7A	NM_001146030.3	c.600+7G>A		splice_region_variant, intron_variant
SEMA7A	XM_047433177.1	c.972+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1095+7G>A		splice_region_variant, intron_variant		1	NM_003612.5	P1
SEMA7A	ENST00000542748.6	c.600+7G>A		splice_region_variant, intron_variant		5
SEMA7A	ENST00000543145.6	c.1053+7G>A		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 251224 Hom.: 3 AF XY: 0.00113 AC XY: 154 AN XY: 135802

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000705 AC: 1031 AN: 1461760 Hom.: 8 Cov.: 32 AF XY: 0.000732 AC XY: 532 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000259

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000761 AC: 116 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74496

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.000778

EpiCase AF: 0.000382

EpiControl AF: 0.000593

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

Jun 12, 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	-0.59
Cadd	Benign	3.5
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0020
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: rs190116829; hg19: chr15-74707172; COSMIC: COSV56089692; COSMIC: COSV56089692;