12-104258027-G-A

Variant names:

• chr12-104258027-G-A
• rs370873183
• NM_001093771.3:c.252G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001093771.3(TXNRD1):​c.252G>A​(p.Lys84Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,548,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TXNRD1 NM_001093771.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33
• Publications: 1 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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-104258027-G-A is Benign according to our data. Variant chr12-104258027-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 728475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD1	NM_001093771.3	c.252G>A	p.Lys84Lys	synonymous_variant	Exon 3 of 17	ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6	c.252G>A	p.Lys84Lys	synonymous_variant	Exon 3 of 17	1	NM_001093771.3	ENSP00000434516.1
TXNRD1	ENST00000526006.1	n.142G>A		non_coding_transcript_exon_variant	Exon 2 of 5	1
TXNRD1	ENST00000534282.1	n.247G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000440 AC: 68 AN: 154584 AF XY: 0.000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000643

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000143 AC: 199 AN: 1395864 Hom.: 0 Cov.: 29 AF XY: 0.000147 AC XY: 101 AN XY: 688498

African (AFR) AF: 0.00 AC: 0 AN: 31604

American (AMR) AF: 0.00177 AC: 61 AN: 34398

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 80 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 36474

South Asian (SAS) AF: 0.00 AC: 0 AN: 77434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.0000408 AC: 44 AN: 1077914

Other (OTH) AF: 0.000242 AC: 14 AN: 57896

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000563

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs370873183; hg19: chr12-104651805;