19-32748510-T-C

Variant names:

• chr19-32748510-T-C
• rs1370192431
• NM_001366102.1:c.475T>C

Variant summary

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

The NM_001366102.1(TDRD12):​c.475T>C​(p.Tyr159His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: TDRD12 NM_001366102.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 publications found

Genes affected

TDRD12 (HGNC:25044): (tudor domain containing 12) Predicted to enable ATP binding activity; RNA helicase activity; and nucleic acid binding activity. Predicted to be involved in several processes, including gamete generation; gene silencing by RNA; and piRNA metabolic process. Predicted to be part of PET complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366102.1. 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
	TDRD12	NM_001366102.1	MANE Select	c.475T>C	p.Tyr159His	missense	Exon 5 of 33	NP_001353031.1	A0A1W2PRK2
	TDRD12	NM_001437947.1		c.475T>C	p.Tyr159His	missense	Exon 5 of 33	NP_001424876.1	A0A2R8Y872
	TDRD12	NM_001438799.1		c.475T>C	p.Tyr159His	missense	Exon 5 of 33	NP_001425728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD12	ENST00000639142.2	TSL:5 MANE Select	c.475T>C	p.Tyr159His	missense	Exon 5 of 33	ENSP00000492643.2	A0A1W2PRK2
	TDRD12	ENST00000444215.6	TSL:1	c.475T>C	p.Tyr159His	missense	Exon 5 of 28	ENSP00000416248.2	Q587J7-1
	TDRD12	ENST00000647536.1		c.475T>C	p.Tyr159His	missense	Exon 5 of 33	ENSP00000496698.1	A0A2R8Y872

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399506 Hom.: 0 Cov.: 30 AF XY: 0.00000435 AC XY: 3 AN XY: 690264

African (AFR) AF: 0.0000633 AC: 2 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078924

Other (OTH) AF: 0.0000516 AC: 3 AN: 58092

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.73	T
PhyloP100		3.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.62		Gain of catalytic residue at I157 (P = 0.075)
MVP		0.081
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.61
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1370192431; hg19: chr19-33239416;