NM_003612.5:c.1382G>C

Variant names:

• chr15-74411925-C-G
• rs376631054
• NM_003612.5:c.1382G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003612.5(SEMA7A):​c.1382G>C​(p.Arg461Pro) 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. 15/22 in silico tools predict a benign outcome for this variant. 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. R461C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 0 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]

SEMA7A Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 11

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19894958).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA7A	NM_003612.5	MANE Select	c.1382G>C	p.Arg461Pro	missense	Exon 11 of 14	NP_003603.1	O75326-1
	SEMA7A	NM_001146029.3		c.1340G>C	p.Arg447Pro	missense	Exon 10 of 13	NP_001139501.1	O75326-2
	SEMA7A	NM_001146030.3		c.887G>C	p.Arg296Pro	missense	Exon 11 of 14	NP_001139502.1	F5GYX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA7A	ENST00000261918.9	TSL:1 MANE Select	c.1382G>C	p.Arg461Pro	missense	Exon 11 of 14	ENSP00000261918.4	O75326-1
	SEMA7A	ENST00000543145.6	TSL:2	c.1340G>C	p.Arg447Pro	missense	Exon 10 of 13	ENSP00000438966.2	O75326-2
	SEMA7A	ENST00000542748.6	TSL:5	c.887G>C	p.Arg296Pro	missense	Exon 11 of 14	ENSP00000441493.1	F5GYX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251194 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		-0.58
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Uncertain	0.040	D
Polyphen		0.94	P
Vest4		0.44
MutPred		0.38		Loss of MoRF binding (P = 0.0503)
MVP		0.64
MPC		1.3
ClinPred		0.40	T
GERP RS		0.38
Varity_R		0.74
gMVP		0.68
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs376631054; hg19: chr15-74704266;