1-145995028-G-C

Variant names:

• chr1-145995028-G-C
• rs782446827
• NM_006472.6:c.475C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006472.6(TXNIP):​c.475C>G​(p.Pro159Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P159S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TXNIP NM_006472.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78

Genes affected

TXNIP (HGNC:16952): (thioredoxin interacting protein) This gene encodes a thioredoxin-binding protein that is a member of the alpha arrestin protein family. Thioredoxin is a thiol-oxidoreductase that is a major regulator of cellular redox signaling which protects cells from oxidative stress. This protein inhibits the antioxidative function of thioredoxin resulting in the accumulation of reactive oxygen species and cellular stress. This protein also functions as a regulator of cellular metabolism and of endoplasmic reticulum (ER) stress. This protein may also function as a tumor suppressor. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNIP	NM_006472.6	c.475C>G	p.Pro159Ala	missense_variant	Exon 4 of 8	ENST00000582401.6	NP_006463.3
TXNIP	NM_001313972.2	c.310C>G	p.Pro104Ala	missense_variant	Exon 3 of 7		NP_001300901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNIP	ENST00000582401.6	c.475C>G	p.Pro159Ala	missense_variant	Exon 4 of 8	1	NM_006472.6	ENSP00000462521.1
TXNIP	ENST00000425134.2	c.310C>G	p.Pro104Ala	missense_variant	Exon 3 of 7	2		ENSP00000396322.2
TXNIP	ENST00000488537.1	n.115C>G		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
LIST_S2	Benign	0.79	T;T
MetaRNN	Pathogenic	0.81	D;D
PROVEAN	Pathogenic	-6.0	.;D
Sift	Uncertain	0.016	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.72
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
gMVP		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782446827; hg19: chr1-145440041;