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GeneBe

2-96861449-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_017789.5(SEMA4C):c.1679C>A(p.Pro560His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,612,628 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25
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 -7 ACMG points.

PP2
Missense variant where missense usually causes diseases, SEMA4C
BP4
Computational evidence support a benign effect (MetaRNN=0.030124992).
BS2
High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA4CNM_017789.5 linkuse as main transcriptc.1679C>A p.Pro560His missense_variant 15/15 ENST00000305476.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA4CENST00000305476.10 linkuse as main transcriptc.1679C>A p.Pro560His missense_variant 15/151 NM_017789.5 P1
SEMA4CENST00000467747.1 linkuse as main transcriptn.1670C>A non_coding_transcript_exon_variant 3/32
SEMA4CENST00000474420.1 linkuse as main transcriptn.912C>A non_coding_transcript_exon_variant 2/22
SEMA4CENST00000482925.5 linkuse as main transcriptn.2069C>A non_coding_transcript_exon_variant 13/132

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152220
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.0000560
AC:
14
AN:
249834
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135370
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000363
AC:
53
AN:
1460408
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
726480
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.000230
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152220
Hom.:
1
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00111
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000957
Alfa
AF:
0.0000844
Hom.:
0
Bravo
AF:
0.000378
ExAC
AF:
0.0000247
AC:
3

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 GeneticsJul 20, 2022The c.1679C>A (p.P560H) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a C to A substitution at nucleotide position 1679, causing the proline (P) at amino acid position 560 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
0.11
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.71
Cadd
Benign
12
Dann
Benign
0.77
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.0070
T
MetaRNN
Benign
0.030
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.11
Sift
Benign
0.10
T
Sift4G
Benign
0.35
T
Polyphen
0.0080
B
Vest4
0.093
MutPred
0.30
Loss of glycosylation at P560 (P = 0.0243);
MVP
0.11
MPC
0.45
ClinPred
0.14
T
GERP RS
0.32
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.037
gMVP
0.50

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: rs747519780; hg19: chr2-97527186; API