15-74410628-T-C

Variant names:

• chr15-74410628-T-C
• rs765620877
• NM_003612.5:c.1997A>G

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.1997A>G​(p.His666Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. H666P) has been classified as Uncertain significance.

• 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: 0.983
• 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=0.16296098).

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.1997A>G	p.His666Arg	missense	Exon 14 of 14	NP_003603.1	O75326-1
	SEMA7A	NM_001146029.3		c.1955A>G	p.His652Arg	missense	Exon 13 of 13	NP_001139501.1	O75326-2
	SEMA7A	NM_001146030.3		c.1502A>G	p.His501Arg	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.1997A>G	p.His666Arg	missense	Exon 14 of 14	ENSP00000261918.4	O75326-1
	SEMA7A	ENST00000543145.6	TSL:2	c.1955A>G	p.His652Arg	missense	Exon 13 of 13	ENSP00000438966.2	O75326-2
	SEMA7A	ENST00000542748.6	TSL:5	c.1502A>G	p.His501Arg	missense	Exon 14 of 14	ENSP00000441493.1	F5GYX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1431872 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707850

African (AFR) AF: 0.00 AC: 0 AN: 33070

American (AMR) AF: 0.00 AC: 0 AN: 43446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24426

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 82542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4706

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093582

Other (OTH) AF: 0.00 AC: 0 AN: 58918

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.98
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.16	B
Vest4		0.23
MutPred		0.38		Loss of catalytic residue at V665 (P = 0.0919)
MVP		0.62
MPC		0.56
ClinPred		0.46	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.64
Mutation Taster		=72/28	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: rs765620877; hg19: chr15-74702969;