8-494576-C-T

Position:

• chr8-494576-C-T

Variant summary

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

The NM_001384899.1(TDRP):​c.130G>A​(p.Gly44Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDRP NM_001384899.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

Genes affected

TDRP (HGNC:26951): (testis development related protein) Acts upstream of or within spermatogenesis. Located in cytosol and nucleus. [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	Protein	UniProt
TDRP	NM_001384899.1	c.130G>A	p.Gly44Ser	missense_variant	2/3	ENST00000324079.11	NP_001371828.1
TDRP	NM_001256113.2	c.130G>A	p.Gly44Ser	missense_variant	2/4		NP_001243042.1
TDRP	NM_175075.5	c.130G>A	p.Gly44Ser	missense_variant	3/4		NP_778250.2
TDRP	XM_047421392.1	c.160G>A	p.Gly54Ser	missense_variant	3/4		XP_047277348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDRP	ENST00000324079.11	c.130G>A	p.Gly44Ser	missense_variant	2/3	1	NM_001384899.1	ENSP00000315111	P1
TDRP	ENST00000523656.5	c.130G>A	p.Gly44Ser	missense_variant	3/5	5		ENSP00000430325
TDRP	ENST00000524229.1	n.61G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

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

May 08, 2024

The c.130G>A (p.G44S) alteration is located in exon 2 (coding exon 2) of the TDRP gene. This alteration results from a G to A substitution at nucleotide position 130, causing the glycine (G) at amino acid position 44 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	0.24
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;.;.
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89
MutPred		0.41		Gain of phosphorylation at G44 (P = 0.0588);Gain of phosphorylation at G44 (P = 0.0588);Gain of phosphorylation at G44 (P = 0.0588);Gain of phosphorylation at G44 (P = 0.0588);
MVP		0.32
MPC		0.011
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.24

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: rs1801077401; hg19: chr8-444576;