rs369653609

Variant names:

• chr1-156154661-C-A
• rs369653609
• NM_022367.4:c.83C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156154661-C-A
• chr1-156154661-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022367.4(SEMA4A):​c.83C>A​(p.Thr28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,036 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. T28M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303

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]

ACMG classification

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=0.08116105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4	c.83C>A	p.Thr28Lys	missense_variant	Exon 2 of 15	ENST00000368285.8	NP_071762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4A	ENST00000368285.8	c.83C>A	p.Thr28Lys	missense_variant	Exon 2 of 15	1	NM_022367.4	ENSP00000357268.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452036 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721308

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.0
DANN	Benign	0.87
DEOGEN2	Benign	0.063	.;.;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.41	T;T;.;.;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.081	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	.;.;L;L;.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.24	T;.;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.011	.;.;B;B;.;B
Vest4		0.35, 0.35, 0.31
MutPred		0.42		Gain of ubiquitination at T28 (P = 0.0177);Gain of ubiquitination at T28 (P = 0.0177);Gain of ubiquitination at T28 (P = 0.0177);Gain of ubiquitination at T28 (P = 0.0177);Gain of ubiquitination at T28 (P = 0.0177);Gain of ubiquitination at T28 (P = 0.0177);
MVP		0.51
MPC		0.20
ClinPred		0.10	T
GERP RS		-1.6
Varity_R		0.058
gMVP		0.46

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: rs369653609; hg19: chr1-156124452;