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GeneBe

2-96861248-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_017789.5(SEMA4C):c.1880G>A(p.Cys627Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SEMA4C
NM_017789.5 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, SEMA4C
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA4CNM_017789.5 linkuse as main transcriptc.1880G>A p.Cys627Tyr missense_variant 15/15 ENST00000305476.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA4CENST00000305476.10 linkuse as main transcriptc.1880G>A p.Cys627Tyr missense_variant 15/151 NM_017789.5 P1
SEMA4CENST00000467747.1 linkuse as main transcriptn.1871G>A non_coding_transcript_exon_variant 3/32
SEMA4CENST00000474420.1 linkuse as main transcriptn.1113G>A non_coding_transcript_exon_variant 2/22
SEMA4CENST00000482925.5 linkuse as main transcriptn.2270G>A non_coding_transcript_exon_variant 13/132

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 18, 2023The c.1880G>A (p.C627Y) 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 1880, causing the cysteine (C) at amino acid position 627 to be replaced by a tyrosine (Y). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.9
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-9.3
D
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.93
Gain of phosphorylation at C627 (P = 0.0534);
MVP
0.53
MPC
1.2
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.95
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-97526985; API