NM_003612.5:c.1040G>C

Variant names:

• chr15-74414893-C-G
• NM_003612.5:c.1040G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003612.5(SEMA7A):​c.1040G>C​(p.Arg347Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA7A	NM_003612.5	c.1040G>C	p.Arg347Pro	missense_variant	Exon 9 of 14	ENST00000261918.9	NP_003603.1
SEMA7A	NM_001146029.3	c.998G>C	p.Arg333Pro	missense_variant	Exon 8 of 13		NP_001139501.1
SEMA7A	NM_001146030.3	c.545G>C	p.Arg182Pro	missense_variant	Exon 9 of 14		NP_001139502.1
SEMA7A	XM_047433177.1	c.917G>C	p.Arg306Pro	missense_variant	Exon 9 of 14		XP_047289133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA7A	ENST00000261918.9	c.1040G>C	p.Arg347Pro	missense_variant	Exon 9 of 14	1	NM_003612.5	ENSP00000261918.4
SEMA7A	ENST00000543145.6	c.998G>C	p.Arg333Pro	missense_variant	Exon 8 of 13	2		ENSP00000438966.2
SEMA7A	ENST00000542748.6	c.545G>C	p.Arg182Pro	missense_variant	Exon 9 of 14	5		ENSP00000441493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.036	D;T;D
Polyphen		1.0	D;.;.
Vest4		0.57
MutPred		0.51		Gain of sheet (P = 0.0221);.;.;
MVP		0.61
MPC		1.6
ClinPred		0.72	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74707234;