9-89319734-C-A

Variant names:

• chr9-89319734-C-A
• rs897562021
• NM_024077.5:c.119C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024077.5(SECISBP2):​c.119C>A​(p.Ala40Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SECISBP2 NM_024077.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.119C>A	p.Ala40Glu	missense	Exon 2 of 17	NP_076982.3
	SECISBP2	NM_001282688.2		c.119C>A	p.Ala40Glu	missense	Exon 2 of 17	NP_001269617.1
	SECISBP2	NM_001354697.2		c.119C>A	p.Ala40Glu	missense	Exon 2 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.119C>A	p.Ala40Glu	missense	Exon 2 of 17	ENSP00000364965.3	Q96T21-1
	SECISBP2	ENST00000339901.8	TSL:1	c.21C>A	p.Ser7Arg	missense	Exon 2 of 17	ENSP00000364959.3	Q96T21-2
	SECISBP2	ENST00000960321.1		c.119C>A	p.Ala40Glu	missense	Exon 2 of 18	ENSP00000630380.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111940

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.75	T
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.050	T
Polyphen		0.99	D
Vest4		0.68
MVP		0.91
MPC		0.34
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.29
gMVP		0.33
Mutation Taster		=273/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs897562021; hg19: chr9-91934649;