chr9-89363482-C-G

Variant names:

• chr9-89363482-C-G
• rs13295305
• ENST00000420101.6:c.293G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142287.2(SEMA4D):​c.2138G>C​(p.Arg713Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SEMA4D NM_001142287.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280

Genes affected

SEMA4D (HGNC:10732): (semaphorin 4D) Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including positive regulation of phosphatidylinositol 3-kinase signaling; regulation of neuron projection development; and regulation of phosphate metabolic process. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SECISBP2 (HGNC:30972): (SECIS binding protein 2) The protein encoded by this gene is one of the essential components of the machinery involved in co-translational insertion of selenocysteine (Sec) into selenoproteins. Sec is encoded by the UGA codon, which normally signals translation termination. The recoding of UGA as Sec codon requires a Sec insertion sequence (SECIS) element; present in the 3' untranslated regions of eukaryotic selenoprotein mRNAs. This protein specifically binds to the SECIS element, which is stimulated by a Sec-specific translation elongation factor. Mutations in this gene have been associated with reduction in enzymatic activity of type II iodothyronine deiodinase (a selenoprotein) and abnormal thyroid hormone metabolism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32741702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4D	NM_001142287.2	c.2138G>C	p.Arg713Thr	missense_variant	Exon 20 of 21		NP_001135759.1
SEMA4D	NM_001371198.1	c.2138G>C	p.Arg713Thr	missense_variant	Exon 18 of 19		NP_001358127.1
SEMA4D	NM_001371199.1	c.2138G>C	p.Arg713Thr	missense_variant	Exon 19 of 20		NP_001358128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4D	ENST00000420101.6	c.293G>C	p.Arg98Thr	missense_variant	Exon 2 of 3	1		ENSP00000399948.2
SEMA4D	ENST00000475255.5	n.2173G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
SEMA4D	ENST00000339861.8	c.2138G>C	p.Arg713Thr	missense_variant	Exon 18 of 19	5		ENSP00000344923.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.95
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.60	.;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-0.32	N;N;D;N
REVEL	Benign	0.021
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.73	P;P;.;P
Vest4		0.62
MutPred		0.45		Loss of MoRF binding (P = 0.0612);Loss of MoRF binding (P = 0.0612);.;Loss of MoRF binding (P = 0.0612);
MVP		0.10
ClinPred		0.85	D
GERP RS		0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13295305; hg19: chr9-91978397;