chr12-104215872-G-A

Variant names:

• chr12-104215872-G-A
• rs1419647714
• NM_001093771.3:c.70G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001093771.3(TXNRD1):​c.70G>A​(p.Gly24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,405,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TXNRD1 NM_001093771.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.502
• Publications: 0 publications found

Genes affected

TXNRD1 (HGNC:12437): (thioredoxin reductase 1) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes an ubiquitously expressed, cytosolic form of TrxR, which functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternative splicing, primarily at the 5' end, results in transcript variants encoding same or different isoforms, including a glutaredoxin-containing isoform that is predominantly expressed in testis. [provided by RefSeq, May 2017]

ENSG00000294348 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055351287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD1	NM_001093771.3	c.70G>A	p.Gly24Ser	missense_variant	Exon 1 of 17	ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6	c.70G>A	p.Gly24Ser	missense_variant	Exon 1 of 17	1	NM_001093771.3	ENSP00000434516.1
ENSG00000294348	ENST00000723050.1	n.57-240C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 152714 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1405370 Hom.: 0 Cov.: 31 AF XY: 0.00000865 AC XY: 6 AN XY: 693948

African (AFR) AF: 0.00 AC: 0 AN: 31796

American (AMR) AF: 0.00 AC: 0 AN: 36224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36220

South Asian (SAS) AF: 0.00 AC: 0 AN: 79532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1083474

Other (OTH) AF: 0.0000172 AC: 1 AN: 58290

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70G>A (p.G24S) alteration is located in exon 1 (coding exon 1) of the TXNRD1 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glycine (G) at amino acid position 24 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.8
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.50
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.095
Sift	Benign	0.61	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0060	B;.
Vest4		0.13
MutPred		0.17		Gain of phosphorylation at G24 (P = 0.0148);Gain of phosphorylation at G24 (P = 0.0148);
MVP		0.44
MPC		0.13
ClinPred		0.036	T
GERP RS		-2.5
PromoterAI		0.14	Neutral
Varity_R		0.037
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1419647714; hg19: chr12-104609650;