chr15-74414893-C-A

Variant names:

• chr15-74414893-C-A
• rs387907241
• NM_003612.5:c.1040G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003612.5(SEMA7A):​c.1040G>T​(p.Arg347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 1.23
• Publications: 6 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003612.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA7A	NM_003612.5	MANE Select	c.1040G>T	p.Arg347Leu	missense	Exon 9 of 14	NP_003603.1
	SEMA7A	NM_001146029.3		c.998G>T	p.Arg333Leu	missense	Exon 8 of 13	NP_001139501.1
	SEMA7A	NM_001146030.3		c.545G>T	p.Arg182Leu	missense	Exon 9 of 14	NP_001139502.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA7A	ENST00000261918.9	TSL:1 MANE Select	c.1040G>T	p.Arg347Leu	missense	Exon 9 of 14	ENSP00000261918.4
	SEMA7A	ENST00000543145.6	TSL:2	c.998G>T	p.Arg333Leu	missense	Exon 8 of 13	ENSP00000438966.2
	SEMA7A	ENST00000542748.6	TSL:5	c.545G>T	p.Arg182Leu	missense	Exon 9 of 14	ENSP00000441493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251304 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000402 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	John Milton Hagen blood group system (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.52	N
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.045	D
Polyphen		0.82	P
Vest4		0.53
MutPred		0.53		Loss of sheet (P = 0.0228)
MVP		0.39
MPC		1.0
ClinPred		0.37	T
GERP RS		5.6
Varity_R		0.54
gMVP		0.68
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: -17

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

Other links and lift over

dbSNP: rs387907241; hg19: chr15-74707234;