9-89325525-CT-C

Variant names:

• chr9-89325525-CT-C
• rs1554716257
• NM_024077.5:c.283delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024077.5(SECISBP2):​c.283delT​(p.Tyr95IlefsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SECISBP2 NM_024077.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.107
• Publications: 1 publications found

Genes affected

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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-89325525-CT-C is Pathogenic according to our data. Variant chr9-89325525-CT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 452803.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024077.5. 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
	SECISBP2	NM_024077.5	MANE Select	c.283delT	p.Tyr95IlefsTer31	frameshift	Exon 3 of 17	NP_076982.3
	SECISBP2	NM_001282688.2		c.283delT	p.Tyr95IlefsTer31	frameshift	Exon 3 of 17	NP_001269617.1
	SECISBP2	NM_001354697.2		c.283delT	p.Tyr95IlefsTer31	frameshift	Exon 3 of 17	NP_001341626.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SECISBP2	ENST00000375807.8	TSL:1 MANE Select	c.283delT	p.Tyr95IlefsTer31	frameshift	Exon 3 of 17	ENSP00000364965.3	Q96T21-1
	SECISBP2	ENST00000339901.8	TSL:1	c.85-21delT		intron	N/A	ENSP00000364959.3	Q96T21-2
	SECISBP2	ENST00000470305.1	TSL:1	n.3328delT		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554716257; hg19: chr9-91940440;