rs55637216

Positions:

• chr15-74417376-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003612.5(SEMA7A):​c.620G>A​(p.Arg207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,613,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: -0.145

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029116422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA7A	NM_003612.5	c.620G>A	p.Arg207Gln	missense_variant	6/14	ENST00000261918.9
SEMA7A	NM_001146029.3	c.578G>A	p.Arg193Gln	missense_variant	5/13
SEMA7A	NM_001146030.3	c.125G>A	p.Arg42Gln	missense_variant	6/14
SEMA7A	XM_047433177.1	c.497G>A	p.Arg166Gln	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA7A	ENST00000261918.9	c.620G>A	p.Arg207Gln	missense_variant	6/14	1	NM_003612.5	P1
SEMA7A	ENST00000543145.6	c.578G>A	p.Arg193Gln	missense_variant	5/13	2
SEMA7A	ENST00000542748.6	c.125G>A	p.Arg42Gln	missense_variant	6/14	5

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000573

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000334 AC: 84 AN: 251408 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135888

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 748 AN: 1461700 Hom.: 1 Cov.: 32 AF XY: 0.000491 AC XY: 357 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000596

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74360

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000491

EpiControl AF: 0.000830

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

John Milton Hagen blood group system Other:1

Affects, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.059	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.23	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.28	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.17
MVP		0.29
MPC		0.53
ClinPred		0.017	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.43

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: rs55637216; hg19: chr15-74709717;