1-154544462-G-A

Variant summary

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

The NM_182499.4(TDRD10):c.742G>A(p.Gly248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TDRD10 NM_182499.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

TDRD10 (HGNC:25316): (tudor domain containing 10) Predicted to enable RNA binding activity. [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, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD10	NM_182499.4	c.742G>A	p.Gly248Arg	missense_variant	10/13	ENST00000368482.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD10	ENST00000368482.8	c.742G>A	p.Gly248Arg	missense_variant	10/13	1	NM_182499.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247782 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460902 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726580

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 09, 2023

The c.742G>A (p.G248R) alteration is located in exon 10 (coding exon 9) of the TDRD10 gene. This alteration results from a G to A substitution at nucleotide position 742, causing the glycine (G) at amino acid position 248 to be replaced by an arginine (R). 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	0.88
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.72
MutPred		0.73		Loss of methylation at R247 (P = 0.1061);Loss of methylation at R247 (P = 0.1061);
MVP		0.23
MPC		1.3
ClinPred		0.65	D
GERP RS		2.2
Varity_R		0.23
gMVP		0.91

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: rs1466812039; hg19: chr1-154516938;