9-110329287-A-T

Variant names:

• chr9-110329287-A-T
• rs747027227
• NM_001424031.1:c.134T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001424031.1(TXNDC8):​c.134T>A​(p.Met45Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,560 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M45V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TXNDC8 NM_001424031.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 0 publications found

Genes affected

TXNDC8 (HGNC:31454): (thioredoxin domain containing 8) Involved in spermatogenesis. Located in Golgi apparatus. Biomarker of male infertility. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000302400 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424031.1. 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
	TXNDC8	NM_001424031.1	MANE Select	c.134T>A	p.Met45Lys	missense	Exon 3 of 6	NP_001410960.1	Q6A555-1
	TXNDC8	NM_001003936.4		c.134T>A	p.Met45Lys	missense	Exon 3 of 6	NP_001003936.1	Q6A555-2
	TXNDC8	NM_001364963.2		c.134T>A	p.Met45Lys	missense	Exon 3 of 5	NP_001351892.1	A0AAA9YHJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC8	ENST00000374511.8	TSL:5 MANE Select	c.134T>A	p.Met45Lys	missense	Exon 3 of 6	ENSP00000363635.3	Q6A555-1
	TXNDC8	ENST00000374510.8	TSL:1	c.134T>A	p.Met45Lys	missense	Exon 3 of 6	ENSP00000363634.4	Q6A555-2
	TXNDC8	ENST00000374507.4	TSL:1	c.130-3047T>A		intron	N/A	ENSP00000363631.4	A9Z1W9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453560 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723324

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108052

Other (OTH) AF: 0.00 AC: 0 AN: 60180

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0070	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.31	T
Polyphen		0.98	D
Vest4		0.73
MutPred		0.87		Loss of stability (P = 0.0293)
MVP		0.22
MPC		0.061
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.94
gMVP		0.69
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs747027227; hg19: chr9-113091567;