10-114199227-G-A

Variant names:

• chr10-114199227-G-A
• rs376849644
• NM_001395205.1:c.439G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395205.1(TDRD1):​c.439G>A​(p.Glu147Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: TDRD1 NM_001395205.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

Genes affected

TDRD1 (HGNC:11712): (tudor domain containing 1) This gene encodes a protein containing a tudor domain that is thought to function in the suppression of transposable elements during spermatogenesis. The related protein in mouse forms a complex with piRNAs and Piwi proteins to promote methylation and silencing of target sequences. This gene was observed to be upregulated by ETS transcription factor ERG in prostate tumors. [provided by RefSeq, Sep 2018]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089003146).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395205.1. 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
	TDRD1	NM_001395205.1	MANE Select	c.439G>A	p.Glu147Lys	missense	Exon 4 of 25	NP_001382134.1	Q9BXT4-1
	TDRD1	NM_001385363.1		c.439G>A	p.Glu147Lys	missense	Exon 4 of 26	NP_001372292.1	Q9BXT4-3
	TDRD1	NM_198795.2		c.439G>A	p.Glu147Lys	missense	Exon 4 of 26	NP_942090.1	Q9BXT4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD1	ENST00000695399.1	MANE Select	c.439G>A	p.Glu147Lys	missense	Exon 4 of 25	ENSP00000511878.1	Q9BXT4-1
	TDRD1	ENST00000251864.7	TSL:1	c.439G>A	p.Glu147Lys	missense	Exon 4 of 26	ENSP00000251864.2	Q9BXT4-3
	TDRD1	ENST00000952550.1		c.439G>A	p.Glu147Lys	missense	Exon 4 of 25	ENSP00000622609.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152014 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251214 AF XY: 0.0000663

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461702 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727142

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111922

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152014 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74238

African (AFR) AF: 0.0000967 AC: 4 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000889 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.029
Sift	Benign	0.24	T
Sift4G	Benign	0.30	T
Polyphen		0.014	B
Vest4		0.11
MVP		0.25
MPC		0.23
ClinPred		0.040	T
GERP RS		4.1
gMVP		0.57
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs376849644; hg19: chr10-115958986;