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GeneBe

5-116447251-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020796.5(SEMA6A):c.2455C>T(p.Pro819Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

SEMA6A
NM_020796.5 missense

Scores

3
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54
Variant links:
Genes affected
SEMA6A (HGNC:10738): (semaphorin 6A) Predicted to enable identical protein binding activity; signaling receptor binding activity; and transmembrane signaling receptor activity. Involved in cellular response to vascular endothelial growth factor stimulus; negative regulation of cell adhesion involved in sprouting angiogenesis; and negative regulation of signal transduction. Predicted to be integral component of membrane. Predicted to be active in extracellular space. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA6ANM_020796.5 linkuse as main transcriptc.2455C>T p.Pro819Ser missense_variant 19/19 ENST00000343348.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA6AENST00000343348.11 linkuse as main transcriptc.2455C>T p.Pro819Ser missense_variant 19/191 NM_020796.5 P4Q9H2E6-1

Frequencies

GnomAD3 genomes
AF:
0.000236
AC:
36
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000964
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000205
AC:
51
AN:
249096
Hom.:
0
AF XY:
0.000222
AC XY:
30
AN XY:
135142
show subpopulations
Gnomad AFR exome
AF:
0.000129
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:
0.000434
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000421
AC:
616
AN:
1461596
Hom.:
0
Cov.:
31
AF XY:
0.000436
AC XY:
317
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000894
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:
0.000528
Gnomad4 OTH exome
AF:
0.000364
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000964
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000426
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000352
Hom.:
0
Bravo
AF:
0.000204
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000357
AC:
3
ExAC
AF:
0.000190
AC:
23
EpiCase
AF:
0.000164
EpiControl
AF:
0.000652

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 27, 2021The c.2455C>T (p.P819S) alteration is located in exon 19 (coding exon 18) of the SEMA6A gene. This alteration results from a C to T substitution at nucleotide position 2455, causing the proline (P) at amino acid position 819 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
Pathogenic
0.66
BayesDel_addAF
Benign
-0.096
T
BayesDel_noAF
Uncertain
-0.050
Cadd
Uncertain
24
Dann
Uncertain
1.0
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Benign
0.054
D
MetaRNN
Uncertain
0.67
D;D;D;D;D
MetaSVM
Uncertain
-0.23
T
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D
REVEL
Uncertain
0.40
Sift
Benign
0.046
D;D;T;T;D
Sift4G
Uncertain
0.024
D;D;D;D;D
Polyphen
1.0
.;.;D;D;.
Vest4
0.73
MVP
0.34
MPC
0.78
ClinPred
0.26
T
GERP RS
5.1
gMVP
0.53

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: rs201027313; hg19: chr5-115782947; COSMIC: COSV56711038; COSMIC: COSV56711038; API