ENST00000420101.6:c.293G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000420101.6(SEMA4D):​c.293G>C​(p.Arg98Thr) 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. 12/17 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. R98K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SEMA4D ENST00000420101.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 15 publications found

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]

SECISBP2 Gene-Disease associations (from GenCC):

• thyroid hormone metabolism, abnormal 1

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• short stature-delayed bone age due to thyroid hormone metabolism deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420101.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4D	NM_001142287.2		c.2138G>C	p.Arg713Thr	missense	Exon 20 of 21	NP_001135759.1	Q92854-2
	SEMA4D	NM_001371198.1		c.2138G>C	p.Arg713Thr	missense	Exon 18 of 19	NP_001358127.1	Q92854-2
	SEMA4D	NM_001371199.1		c.2138G>C	p.Arg713Thr	missense	Exon 19 of 20	NP_001358128.1	Q92854-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4D	ENST00000420101.6	TSL:1	c.293G>C	p.Arg98Thr	missense	Exon 2 of 3	ENSP00000399948.2
	SEMA4D	ENST00000475255.5	TSL:1	n.2173G>C		non_coding_transcript_exon	Exon 1 of 2
	SEMA4D	ENST00000339861.8	TSL:5	c.2138G>C	p.Arg713Thr	missense	Exon 18 of 19	ENSP00000344923.4	Q92854-2

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
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
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.28
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.021
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		0.73	P
Vest4		0.62
MutPred		0.45		Loss of MoRF binding (P = 0.0612)
MVP		0.10
ClinPred		0.85	D
GERP RS		0.79
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs13295305; hg19: chr9-91978397;