1-151774806-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001083965.2(TDRKH):c.1537G>T(p.Ala513Ser) variant causes a missense, splice region 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. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDRKH NM_001083965.2 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRKH	NM_001083965.2	c.1537G>T	p.Ala513Ser	missense_variant, splice_region_variant	12/13	ENST00000368824.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRKH	ENST00000368824.8	c.1537G>T	p.Ala513Ser	missense_variant, splice_region_variant	12/13	1	NM_001083965.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 11, 2022

The c.1537G>T (p.A513S) alteration is located in exon 12 (coding exon 11) of the TDRKH gene. This alteration results from a G to T substitution at nucleotide position 1537, causing the alanine (A) at amino acid position 513 to be replaced by a serine (S). 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	Benign	0.085
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0097	T;.;.;T;.;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0036
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.;M;M
MutationTaster	Benign	0.83	D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.090	N;.;N;N;N;N;N
REVEL	Benign	0.035
Sift	Uncertain	0.015	D;.;D;D;D;D;D
Sift4G	Benign	0.44	T;T;T;T;T;T;T
Polyphen		0.52	P;.;.;P;P;P;P
Vest4		0.26
MutPred		0.27		Gain of phosphorylation at A513 (P = 0.0233);Gain of phosphorylation at A513 (P = 0.0233);.;Gain of phosphorylation at A513 (P = 0.0233);.;Gain of phosphorylation at A513 (P = 0.0233);Gain of phosphorylation at A513 (P = 0.0233);
MVP		0.37
MPC		0.35
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.070
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.070		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: rs1648994252; hg19: chr1-151747282;