13-60510647-G-A

Variant names:

• chr13-60510647-G-A
• NM_001146070.2:c.1033G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001146070.2(TDRD3):​c.1033G>A​(p.Gly345Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,318 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: 6.9e-7 (0 hom.)
• Consequence: TDRD3 NM_001146070.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.16
• Publications: 0 publications found

Genes affected

TDRD3 (HGNC:20612): (tudor domain containing 3) Enables chromatin binding activity; methylated histone binding activity; and transcription coactivator activity. Predicted to be involved in chromatin organization and positive regulation of transcription, DNA-templated. Located in Golgi apparatus; cytosol; and nucleoplasm. Colocalizes with exon-exon junction complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146070.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD3	NM_001146070.2	MANE Select	c.1033G>A	p.Gly345Arg	missense	Exon 10 of 14	NP_001139542.1	Q9H7E2-3
	TDRD3	NM_001146071.1		c.754G>A	p.Gly252Arg	missense	Exon 10 of 14	NP_001139543.1	Q9H7E2-1
	TDRD3	NM_030794.2		c.754G>A	p.Gly252Arg	missense	Exon 10 of 14	NP_110421.1	Q9H7E2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD3	ENST00000377881.8	TSL:1 MANE Select	c.1033G>A	p.Gly345Arg	missense	Exon 10 of 14	ENSP00000367113.2	Q9H7E2-3
	TDRD3	ENST00000196169.7	TSL:1	c.754G>A	p.Gly252Arg	missense	Exon 10 of 14	ENSP00000196169.3	Q9H7E2-1
	TDRD3	ENST00000621840.4	TSL:1	c.751G>A	p.Gly251Arg	missense	Exon 10 of 14	ENSP00000477993.1	Q9H7E2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449318 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720930

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 43180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 83614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105898

Other (OTH) AF: 0.00 AC: 0 AN: 59794

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.39		Gain of solvent accessibility (P = 0.0055)
MVP		0.99
MPC		0.72
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.30
gMVP		0.44
Mutation Taster		=32/68	disease causing

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

Other links and lift over

hg19: chr13-61084781; COSMIC: COSV105055176;