5-116447251-G-A

Variant names:

• chr5-116447251-G-A
• rs201027313
• NM_020796.5:c.2455C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.54

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]

SEMA6A-AS1 (HGNC:51110): (SEMA6A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6A	NM_020796.5	c.2455C>T	p.Pro819Ser	missense_variant	Exon 19 of 19	ENST00000343348.11	NP_065847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6A	ENST00000343348.11	c.2455C>T	p.Pro819Ser	missense_variant	Exon 19 of 19	1	NM_020796.5	ENSP00000345512.6

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152248 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000205 AC: 51 AN: 249096 AF XY: 0.000222

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 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

Gnomad4 AFR exome AF: 0.0000896 AC: 3 AN: 33480

Gnomad4 AMR exome AF: 0.0000894 AC: 4 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53290

Gnomad4 NFE exome AF: 0.000528 AC: 587 AN: 1111868

Gnomad4 Remaining exome AF: 0.000364 AC: 22 AN: 60374

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74378

Gnomad4 AFR AF: 0.0000964 AC: 0.0000964413 AN: 0.0000964413

Gnomad4 AMR AF: 0.000131 AC: 0.000130804 AN: 0.000130804

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000426 AC: 0.000426232 AN: 0.000426232

Gnomad4 OTH AF: 0.000478 AC: 0.000478011 AN: 0.000478011

Alfa AF: 0.000405 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

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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
DEOGEN2	Benign	0.11	.;T;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
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
Mutation Taster		=15/85	disease causing

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

Other links and lift over

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