1-179592844-A-C

Variant names:

• chr1-179592844-A-C
• rs1254296087
• NM_001199085.3:c.229A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001199085.3(TDRD5):​c.229A>C​(p.Lys77Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDRD5 NM_001199085.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

Genes affected

TDRD5 (HGNC:20614): (tudor domain containing 5) Predicted to be involved in DNA methylation involved in gamete generation; P granule organization; and spermatid development. Predicted to be located in chromatoid body and pi-body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.308272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD5	NM_001199085.3	c.229A>C	p.Lys77Gln	missense_variant	Exon 2 of 18	ENST00000444136.6	NP_001186014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD5	ENST00000444136.6	c.229A>C	p.Lys77Gln	missense_variant	Exon 2 of 18	1	NM_001199085.3	ENSP00000406052.1
TDRD5	ENST00000294848.12	c.229A>C	p.Lys77Gln	missense_variant	Exon 2 of 17	1		ENSP00000294848.8
TDRD5	ENST00000367614.5	c.229A>C	p.Lys77Gln	missense_variant	Exon 2 of 17	2		ENSP00000356586.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229A>C (p.K77Q) alteration is located in exon 2 (coding exon 1) of the TDRD5 gene. This alteration results from a A to C substitution at nucleotide position 229, causing the lysine (K) at amino acid position 77 to be replaced by a glutamine (Q). 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	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T;.;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.049	D;T;D
Sift4G	Benign	0.066	T;T;T
Polyphen		0.91	P;D;P
Vest4		0.41
MutPred		0.49		Loss of methylation at K77 (P = 0.0034);Loss of methylation at K77 (P = 0.0034);Loss of methylation at K77 (P = 0.0034);
MVP		0.068
MPC		0.38
ClinPred		0.76	D
GERP RS		4.4
Varity_R		0.22
gMVP		0.62

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: rs1254296087; hg19: chr1-179561979;