Genetic Variant SEMA4C:p.Ser760Trp (chr2-96860849-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017789.5(SEMA4C):c.2279C>G(p.Ser760Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S760L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4C	NM_017789.5 link	c.2279C>G	p.Ser760Trp	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.2279C>G	p.Ser760Trp	missense_variant	Exon 15 of 15	1	NM_017789.5	ENSP00000306844.5	Q9C0C4
SEMA4C	ENST00000467747.1 link	n.2270C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
SEMA4C	ENST00000474420.1 link	n.1512C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEMA4C	ENST00000482925.5 link	n.2669C>G		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249762

AF XY:

0.00000738

show subpopulations

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

0.075

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.69

PhyloP100

1.9

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.46

MutPred

0.23

Loss of glycosylation at S760 (P = 0.0059);

MVP

0.47

MPC

1.2

ClinPred

0.76

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.36

Mutation Taster

=87/13

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over