9-89363868-G-A

Variant names:

• chr9-89363868-G-A
• rs45515192
• ENST00000420101.6:c.120C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001142287.2(SEMA4D):​c.1965C>T​(p.Pro655Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,614,018 control chromosomes in the GnomAD database, including 20,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1777 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18333 hom.)
• Consequence: SEMA4D NM_001142287.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.50
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-89363868-G-A is Benign according to our data. Variant chr9-89363868-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060340.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.286 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.1965C>T	p.Pro655Pro	synonymous	Exon 19 of 21	NP_001135759.1	Q92854-2
	SEMA4D	NM_001371198.1		c.1965C>T	p.Pro655Pro	synonymous	Exon 17 of 19	NP_001358127.1	Q92854-2
	SEMA4D	NM_001371199.1		c.1965C>T	p.Pro655Pro	synonymous	Exon 18 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.120C>T	p.Pro40Pro	synonymous	Exon 1 of 3	ENSP00000399948.2
	SEMA4D	ENST00000475255.5	TSL:1	n.1787C>T		non_coding_transcript_exon	Exon 1 of 2
	SEMA4D	ENST00000339861.8	TSL:5	c.1965C>T	p.Pro655Pro	synonymous	Exon 17 of 19	ENSP00000344923.4	Q92854-2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18808 AN: 152144 Hom.: 1769 Cov.: 33

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.176 AC: 44288 AN: 251246 AF XY: 0.166

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0823

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.145 AC: 211597 AN: 1461756 Hom.: 18333 Cov.: 33 AF XY: 0.143 AC XY: 103814 AN XY: 727166

African (AFR) AF: 0.0234 AC: 784 AN: 33478

American (AMR) AF: 0.434 AC: 19408 AN: 44716

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

East Asian (EAS) AF: 0.158 AC: 6278 AN: 39700

South Asian (SAS) AF: 0.135 AC: 11606 AN: 86256

European-Finnish (FIN) AF: 0.159 AC: 8500 AN: 53300

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154847 AN: 1112010

Other (OTH) AF: 0.130 AC: 7840 AN: 60392

GnomAD4 genome AF: 0.124 AC: 18828 AN: 152262 Hom.: 1777 Cov.: 33 AF XY: 0.127 AC XY: 9488 AN XY: 74434

African (AFR) AF: 0.0310 AC: 1288 AN: 41570

American (AMR) AF: 0.294 AC: 4488 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5162

South Asian (SAS) AF: 0.135 AC: 651 AN: 4830

European-Finnish (FIN) AF: 0.141 AC: 1496 AN: 10606

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

European-Non Finnish (NFE) AF: 0.135 AC: 9168 AN: 68020

Other (OTH) AF: 0.112 AC: 237 AN: 2116

Alfa AF: 0.0954 Hom.: 346

Bravo AF: 0.133

Asia WGS AF: 0.192 AC: 665 AN: 3478

EpiCase AF: 0.119

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	0.096
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.075
DANN	Benign	0.68
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs45515192; hg19: chr9-91978783; COSMIC: COSV59392394; COSMIC: COSV59392394;