18-9887125-C-G

Variant names:

• chr18-9887125-C-G
• rs147948919
• NM_032243.6:c.445C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032243.6(TXNDC2):​c.445C>G​(p.Pro149Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. P149S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: TXNDC2 NM_032243.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29
• Publications: 0 publications found

Genes affected

TXNDC2 (HGNC:16470): (thioredoxin domain containing 2) Enables thioredoxin-disulfide reductase activity. Predicted to be involved in cell differentiation and cellular oxidant detoxification. Predicted to act upstream of or within cellular response to reactive oxygen species and flagellated sperm motility. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072006345).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032243.6. 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
	TXNDC2	NM_032243.6	MANE Select	c.445C>G	p.Pro149Ala	missense	Exon 2 of 2	NP_115619.4
	TXNDC2	NM_001098529.2		c.646C>G	p.Pro216Ala	missense	Exon 2 of 2	NP_001091999.1	A0A140VJY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC2	ENST00000357775.6	TSL:1 MANE Select	c.445C>G	p.Pro149Ala	missense	Exon 2 of 2	ENSP00000350419.4	Q86VQ3-2
	TXNDC2	ENST00000306084.6	TSL:1	c.646C>G	p.Pro216Ala	missense	Exon 2 of 2	ENSP00000304908.6	Q86VQ3-1
	TXNDC2	ENST00000536353.2	TSL:5	c.328+117C>G		intron	N/A	ENSP00000437393.2	F5H6S7

Frequencies

GnomAD3 genomes AF: 0.00000709 AC: 1 AN: 141128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 130

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000708 AC: 1 AN: 141256 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37672

American (AMR) AF: 0.00 AC: 0 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4384

South Asian (SAS) AF: 0.00 AC: 0 AN: 4278

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64710

Other (OTH) AF: 0.00 AC: 0 AN: 1934

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.010
DANN	Benign	0.38
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.3	L
PhyloP100		-2.3
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.27
Sift	Benign	0.40	T
Sift4G	Benign	0.21	T
Polyphen		0.15	B
Vest4		0.049
MutPred		0.19		Gain of MoRF binding (P = 0.0446)
MVP		0.30
MPC		0.098
ClinPred		0.23	T
GERP RS		-5.0
Varity_R		0.018
gMVP		0.033
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147948919; hg19: chr18-9887122;