2-96860903-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_017789.5(SEMA4C):ā€‹c.2225C>Gā€‹(p.Ser742Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,838 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 (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.37
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_benign. Variant got -3 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity SEM4C_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.40050715).
BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SEMA4CNM_017789.5 linkuse as main transcriptc.2225C>G p.Ser742Cys missense_variant 15/15 ENST00000305476.10 NP_060259.4 Q9C0C4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SEMA4CENST00000305476.10 linkuse as main transcriptc.2225C>G p.Ser742Cys missense_variant 15/151 NM_017789.5 ENSP00000306844.5 Q9C0C4
SEMA4CENST00000467747.1 linkuse as main transcriptn.2216C>G non_coding_transcript_exon_variant 3/32
SEMA4CENST00000474420.1 linkuse as main transcriptn.1458C>G non_coding_transcript_exon_variant 2/22
SEMA4CENST00000482925.5 linkuse as main transcriptn.2615C>G non_coding_transcript_exon_variant 13/132

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249422
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135444
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 SAS 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:
0.0000164
AC:
24
AN:
1460838
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
726726
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000165
AC:
2

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 GeneticsFeb 16, 2023The c.2225C>G (p.S742C) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a C to G substitution at nucleotide position 2225, causing the serine (S) at amino acid position 742 to be replaced by a cysteine (C). 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
Uncertain
0.39
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
0.97
DEOGEN2
Benign
0.074
T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.40
T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
0.81
L
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.25
N
REVEL
Uncertain
0.35
Sift
Benign
0.17
T
Sift4G
Benign
0.15
T
Polyphen
1.0
D
Vest4
0.51
MutPred
0.17
Gain of catalytic residue at L743 (P = 0.0439);
MVP
0.52
MPC
0.98
ClinPred
0.37
T
GERP RS
5.1
Varity_R
0.25
gMVP
0.55

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769665682; hg19: chr2-97526640; API