1-151775533-C-G

Position:

• chr1-151775533-C-G

Variant summary

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

The NM_001083965.2(TDRKH):​c.1293G>C​(p.Trp431Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TDRKH NM_001083965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

Genes affected

TDRKH (HGNC:11713): (tudor and KH domain containing) Predicted to enable RNA binding activity. Predicted to be involved in fertilization; gamete generation; and piRNA metabolic process. Predicted to be located in mitochondrion; pi-body; and piP-body. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDRKH	NM_001083965.2	c.1293G>C	p.Trp431Cys	missense_variant	10/13	ENST00000368824.8	NP_001077434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDRKH	ENST00000368824.8	c.1293G>C	p.Trp431Cys	missense_variant	10/13	1	NM_001083965.2	ENSP00000357815	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460618 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.1293G>C (p.W431C) alteration is located in exon 10 (coding exon 9) of the TDRKH gene. This alteration results from a G to C substitution at nucleotide position 1293, causing the tryptophan (W) at amino acid position 431 to be replaced by a cysteine (C). 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;T;.;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	.;D;D;.;D;.;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.9	M;.;.;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-12	D;.;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;D;D
Vest4		0.93
MutPred		0.60		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);.;Gain of loop (P = 0.0312);.;Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.66
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1412079096; hg19: chr1-151748009;