2-96860925-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017789.5(SEMA4C):​c.2203G>A​(p.Gly735Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,958 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000076 ( 2 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03994158).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SEMA4CNM_017789.5 linkuse as main transcriptc.2203G>A p.Gly735Ser 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.2203G>A p.Gly735Ser missense_variant 15/151 NM_017789.5 ENSP00000306844.5 Q9C0C4
SEMA4CENST00000467747.1 linkuse as main transcriptn.2194G>A non_coding_transcript_exon_variant 3/32
SEMA4CENST00000474420.1 linkuse as main transcriptn.1436G>A non_coding_transcript_exon_variant 2/22
SEMA4CENST00000482925.5 linkuse as main transcriptn.2593G>A non_coding_transcript_exon_variant 13/132

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000124
AC:
31
AN:
249058
Hom.:
0
AF XY:
0.000185
AC XY:
25
AN XY:
135358
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:
0.000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000760
AC:
111
AN:
1460772
Hom.:
2
Cov.:
31
AF XY:
0.000111
AC XY:
81
AN XY:
726700
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00112
Gnomad4 FIN exome
AF:
0.0000191
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000277
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

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 GeneticsOct 08, 2024The c.2203G>A (p.G735S) 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 2203, causing the glycine (G) at amino acid position 735 to be replaced by a serine (S). 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
0.091
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.051
T
Eigen
Benign
-0.081
Eigen_PC
Benign
0.083
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.040
T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
-0.20
N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.12
N
REVEL
Benign
0.22
Sift
Benign
0.30
T
Sift4G
Benign
0.51
T
Polyphen
0.82
P
Vest4
0.066
MutPred
0.20
Gain of sheet (P = 0.0344);
MVP
0.27
MPC
0.29
ClinPred
0.077
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.18
gMVP
0.18

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: rs766822299; hg19: chr2-97526662; COSMIC: COSV59690133; COSMIC: COSV59690133; API