rs12471298

Positions:

• chr2-96861051-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_017789.5(SEMA4C):​c.2077G>T​(p.Glu693Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,612,808 control chromosomes in the GnomAD database, including 1,114 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (126 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (988 hom.)
• Consequence: SEMA4C NM_017789.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

Genes affected

SEMA4C (HGNC:10731): (semaphorin 4C) Predicted to enable chemorepellent activity and semaphorin receptor binding activity. Involved in muscle cell differentiation and positive regulation of stress-activated MAPK cascade. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.17 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4C	NM_017789.5	c.2077G>T	p.Glu693Ter	stop_gained	15/15	ENST00000305476.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4C	ENST00000305476.10	c.2077G>T	p.Glu693Ter	stop_gained	15/15	1	NM_017789.5	P1
SEMA4C	ENST00000467747.1	n.2068G>T		non_coding_transcript_exon_variant	3/3	2
SEMA4C	ENST00000474420.1	n.1310G>T		non_coding_transcript_exon_variant	2/2	2
SEMA4C	ENST00000482925.5	n.2467G>T		non_coding_transcript_exon_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1756 AN: 152182 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0298 AC: 7393 AN: 248396 Hom.: 815 AF XY: 0.0217 AC XY: 2937 AN XY: 135090

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00387

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.00645 AC: 9426 AN: 1460508 Hom.: 988 Cov.: 31 AF XY: 0.00530 AC XY: 3853 AN XY: 726544

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00320

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.0116 AC: 1770 AN: 152300 Hom.: 126 Cov.: 33 AF XY: 0.0121 AC XY: 898 AN XY: 74478

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00327

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00114 Hom.: 15

Bravo AF: 0.0235

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0226 AC: 2742

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	2.9e-22	P
Vest4		0.48
GERP RS		4.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs12471298; hg19: chr2-97526788; COSMIC: COSV59690275; COSMIC: COSV59690275;