9-89363482-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001142287.2(SEMA4D):​c.2138G>A​(p.Arg713Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,984 control chromosomes in the GnomAD database, including 20,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1809 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18448 hom.)
• Consequence: SEMA4D NM_001142287.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0554357E-4).
• BP6: Variant 9-89363482-C-T is Benign according to our data. Variant chr9-89363482-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060820.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142287.2. 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>A	p.Arg713Lys	missense	Exon 20 of 21	NP_001135759.1	Q92854-2
	SEMA4D	NM_001371198.1		c.2138G>A	p.Arg713Lys	missense	Exon 18 of 19	NP_001358127.1	Q92854-2
	SEMA4D	NM_001371199.1		c.2138G>A	p.Arg713Lys	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>A	p.Arg98Lys	missense	Exon 2 of 3	ENSP00000399948.2
	SEMA4D	ENST00000475255.5	TSL:1	n.2173G>A		non_coding_transcript_exon	Exon 1 of 2
	SEMA4D	ENST00000339861.8	TSL:5	c.2138G>A	p.Arg713Lys	missense	Exon 18 of 19	ENSP00000344923.4	Q92854-2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19385 AN: 152144 Hom.: 1801 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.178 AC: 44590 AN: 251200 AF XY: 0.167

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.145 AC: 212484 AN: 1461722 Hom.: 18448 Cov.: 33 AF XY: 0.143 AC XY: 104305 AN XY: 727170

African (AFR) AF: 0.0364 AC: 1218 AN: 33480

American (AMR) AF: 0.435 AC: 19451 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 2175 AN: 26136

East Asian (EAS) AF: 0.159 AC: 6294 AN: 39700

South Asian (SAS) AF: 0.137 AC: 11847 AN: 86256

European-Finnish (FIN) AF: 0.159 AC: 8496 AN: 53282

Middle Eastern (MID) AF: 0.0290 AC: 167 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154925 AN: 1111994

Other (OTH) AF: 0.131 AC: 7911 AN: 60388

GnomAD4 genome AF: 0.127 AC: 19410 AN: 152262 Hom.: 1809 Cov.: 33 AF XY: 0.131 AC XY: 9771 AN XY: 74448

African (AFR) AF: 0.0433 AC: 1798 AN: 41566

American (AMR) AF: 0.295 AC: 4516 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1048 AN: 5164

South Asian (SAS) AF: 0.136 AC: 658 AN: 4830

European-Finnish (FIN) AF: 0.141 AC: 1500 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9196 AN: 67998

Other (OTH) AF: 0.114 AC: 240 AN: 2114

Alfa AF: 0.125 Hom.: 2324

Bravo AF: 0.136

TwinsUK AF: 0.130 AC: 482

ALSPAC AF: 0.141 AC: 544

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.133 AC: 1147

ExAC AF: 0.163 AC: 19730

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.121

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SEMA4D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.95
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.00091	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.28
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.026
Sift	Benign	0.47	T
Sift4G	Benign	0.42	T
Polyphen		0.0040	B
Vest4		0.10
ClinPred		0.0021	T
GERP RS		0.79
Mutation Taster		=98/2	polymorphism (auto)

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; COSMIC: COSV59394932; COSMIC: COSV59394932;