Genetic Variant SEMA4C:p.Arg791His (chr2-96860756-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_017789.5(SEMA4C):c.2372G>A(p.Arg791His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Publications

1 publications found

Variant links:

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]

SEMA4C links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3799036).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4C	NM_017789.5 link	c.2372G>A	p.Arg791His	missense_variant	Exon 15 of 15	ENST00000305476.10	NP_060259.4	Q9C0C4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SEMA4C	ENST00000305476.10 link	c.2372G>A	p.Arg791His	missense_variant	Exon 15 of 15	1	NM_017789.5	ENSP00000306844.5	Q9C0C4
SEMA4C	ENST00000467747.1 link	n.2363G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
SEMA4C	ENST00000474420.1 link	n.1605G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEMA4C	ENST00000482925.5 link	n.2762G>A		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2372G>A (p.R791H) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a G to A substitution at nucleotide position 2372, causing the arginine (R) at amino acid position 791 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.038

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

2.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.8

REVEL

Benign

0.23

Sift

Benign

0.037

Sift4G

Uncertain

0.050

Polyphen

1.0

Vest4

0.49

MutPred

0.55

Loss of MoRF binding (P = 0.0126);

MVP

0.23

MPC

1.1

ClinPred

0.89

GERP RS

4.9

Varity_R

0.11

gMVP

0.47

Mutation Taster

=57/43

polymorphism

(source)

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

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2-96860756-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over