Genetic Variant SEMA6A:p.Thr996Ser (chr5-116446720-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020796.5(SEMA6A):c.2986A>T(p.Thr996Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,600,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

SEMA6A
NM_020796.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

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]

SEMA6A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11256477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6A	NM_020796.5 link	c.2986A>T	p.Thr996Ser	missense_variant	Exon 19 of 19	ENST00000343348.11	NP_065847.1	Q9H2E6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6A	ENST00000343348.11 link	c.2986A>T	p.Thr996Ser	missense_variant	Exon 19 of 19	1	NM_020796.5	ENSP00000345512.6		Q9H2E6-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000132

AC:

AN:

227122

Hom.:

AF XY:

0.00000814

AC XY:

AN XY:

122924

show subpopulations

Gnomad AFR exome

AF:

0.000220

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000829

AC:

AN:

1447934

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

718812

show subpopulations

Gnomad4 AFR exome

AF:

0.000300

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000118

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2986A>T (p.T996S) alteration is located in exon 19 (coding exon 18) of the SEMA6A gene. This alteration results from a A to T substitution at nucleotide position 2986, causing the threonine (T) at amino acid position 996 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

0.072

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.010

.;T;T;.;.

Eigen

Benign

-0.050

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.79

.;T;T;T;.

M_CAP

Benign

0.0064

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.47

N;N;N;N;N

REVEL

Benign

0.088

Sift

Benign

0.45

T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T

Polyphen

0.0040, 0.0010

.;.;B;B;.

Vest4

0.081

MutPred

0.11

Gain of glycosylation at T996 (P = 0.1336);.;.;.;Gain of glycosylation at T996 (P = 0.1336);

MVP

0.27

MPC

0.18

ClinPred

0.11

GERP RS

4.4

gMVP

0.23

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over