NM_003612.5:c.1945G>C

Variant names:

• chr15-74410680-C-G
• rs757652732
• NM_003612.5:c.1945G>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.1945G>C​(p.Ala649Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A649T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.38
• Publications: 2 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=0.12623161).

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.1945G>C	p.Ala649Pro	missense	Exon 14 of 14	NP_003603.1	O75326-1
	SEMA7A	NM_001146029.3		c.1903G>C	p.Ala635Pro	missense	Exon 13 of 13	NP_001139501.1	O75326-2
	SEMA7A	NM_001146030.3		c.1450G>C	p.Ala484Pro	missense	Exon 14 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.1945G>C	p.Ala649Pro	missense	Exon 14 of 14	ENSP00000261918.4	O75326-1
	SEMA7A	ENST00000543145.6	TSL:2	c.1903G>C	p.Ala635Pro	missense	Exon 13 of 13	ENSP00000438966.2	O75326-2
	SEMA7A	ENST00000542748.6	TSL:5	c.1450G>C	p.Ala484Pro	missense	Exon 14 of 14	ENSP00000441493.1	F5GYX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249098 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723886

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000224 AC: 1 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108482

Other (OTH) AF: 0.00 AC: 0 AN: 60134

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.012
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-2.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.12
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.025	D
Polyphen		0.48	P
Vest4		0.18
MutPred		0.69		Loss of catalytic residue at A649 (P = 0.0419)
MVP		0.37
MPC		0.98
ClinPred		0.11	T
GERP RS		-2.0
Varity_R		0.11
gMVP		0.87

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: rs757652732; hg19: chr15-74703021;