NM_003612.5:c.1738A>G

Variant names:

• chr15-74410887-T-C
• rs1191144877
• NM_003612.5:c.1738A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003612.5(SEMA7A):​c.1738A>G​(p.Lys580Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02642399).
• BP6: Variant 15-74410887-T-C is Benign according to our data. Variant chr15-74410887-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3439612.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA7A	NM_003612.5	c.1738A>G	p.Lys580Glu	missense_variant	Exon 14 of 14	ENST00000261918.9	NP_003603.1
SEMA7A	NM_001146029.3	c.1696A>G	p.Lys566Glu	missense_variant	Exon 13 of 13		NP_001139501.1
SEMA7A	NM_001146030.3	c.1243A>G	p.Lys415Glu	missense_variant	Exon 14 of 14		NP_001139502.1
SEMA7A	XM_047433177.1	c.1615A>G	p.Lys539Glu	missense_variant	Exon 14 of 14		XP_047289133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1738A>G	p.Lys580Glu	missense_variant	Exon 14 of 14	1	NM_003612.5	ENSP00000261918.4
SEMA7A	ENST00000543145.6	c.1696A>G	p.Lys566Glu	missense_variant	Exon 13 of 13	2		ENSP00000438966.2
SEMA7A	ENST00000542748.6	c.1243A>G	p.Lys415Glu	missense_variant	Exon 14 of 14	5		ENSP00000441493.1
SEMA7A	ENST00000569617.1	n.*81A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 13, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.50
DEOGEN2	Benign	0.049	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.035	N;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.52	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.051
MutPred		0.41		Loss of ubiquitination at K580 (P = 0.0074);.;.;
MVP		0.33
MPC		0.64
ClinPred		0.057	T
GERP RS		-0.042
Varity_R		0.21
gMVP		0.57

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: rs1191144877; hg19: chr15-74703228;