NM_003612.5:c.1419G>C

Variant names:

• chr15-74411888-C-G
• rs1315805550
• NM_003612.5:c.1419G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003612.5(SEMA7A):​c.1419G>C​(p.Glu473Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,502 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SEMA7A NM_003612.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07909405).
• BP6: Variant 15-74411888-C-G is Benign according to our data. Variant chr15-74411888-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2318638.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1419G>C	p.Glu473Asp	missense	Exon 11 of 14	NP_003603.1	O75326-1
	SEMA7A	NM_001146029.3		c.1377G>C	p.Glu459Asp	missense	Exon 10 of 13	NP_001139501.1	O75326-2
	SEMA7A	NM_001146030.3		c.924G>C	p.Glu308Asp	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.1419G>C	p.Glu473Asp	missense	Exon 11 of 14	ENSP00000261918.4	O75326-1
	SEMA7A	ENST00000543145.6	TSL:2	c.1377G>C	p.Glu459Asp	missense	Exon 10 of 13	ENSP00000438966.2	O75326-2
	SEMA7A	ENST00000542748.6	TSL:5	c.924G>C	p.Glu308Asp	missense	Exon 11 of 14	ENSP00000441493.1	F5GYX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250814 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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461502 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727050

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: 26126

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.074
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.1
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.027
Sift	Benign	0.58	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.33		Loss of sheet (P = 0.0181)
MVP		0.37
MPC		0.41
ClinPred		0.035	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.42

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: rs1315805550; hg19: chr15-74704229;