dbSNP rs1045906206: SEMA4A:p.Thr29Arg (chr1-156154664-C-G) – 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_022367.4(SEMA4A):c.86C>G(p.Thr29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T29M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SEMA4A
NM_022367.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.575

Variant links:

Genes affected

SEMA4A (HGNC:10729): (semaphorin 4A) This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

SEMA4A links:

Genome browser will be placed here

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=0.10987866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4 link	c.86C>G	p.Thr29Arg	missense_variant	Exon 2 of 15	ENST00000368285.8	NP_071762.2	Q9H3S1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4A	ENST00000368285.8 link	c.86C>G	p.Thr29Arg	missense_variant	Exon 2 of 15	1	NM_022367.4	ENSP00000357268.3		Q9H3S1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000441

AC:

AN:

226982

Hom.:

AF XY:

0.00000814

AC XY:

AN XY:

122900

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000980

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451392

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

720936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.88

DANN

Benign

0.93

DEOGEN2

Benign

0.063

.;.;T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.40

T;T;.;.;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.11

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;L;L;.;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.064

T;.;T;T;T;T

Sift4G

Benign

0.60

T;T;T;T;T;T

Polyphen

0.64

.;.;P;P;.;P

Vest4

0.44, 0.44, 0.38

MutPred

0.42

Gain of methylation at T29 (P = 0.0122);Gain of methylation at T29 (P = 0.0122);Gain of methylation at T29 (P = 0.0122);Gain of methylation at T29 (P = 0.0122);Gain of methylation at T29 (P = 0.0122);Gain of methylation at T29 (P = 0.0122);

MVP

0.31

MPC

0.36

ClinPred

0.095

GERP RS

-0.49

Varity_R

0.085

gMVP

0.52

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over