chr15-70892125-G-A

Position:

• chr15-70892125-G-A

Variant summary

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

The NM_020147.4(THAP10):​c.148C>T​(p.Arg50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: THAP10 NM_020147.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705

Genes affected

THAP10 (HGNC:23193): (THAP domain containing 10) This gene encodes a member of a family of proteins sharing an N-terminal Thanatos-associated domain. The Thanatos-associated domain contains a zinc finger signature similar to DNA-binding domains. This gene is part of a bidirectional gene pair on the long arm of chromosome 15 that is regulated by estrogen and may play a role in breast cancer. [provided by RefSeq, Nov 2010]

LRRC49 (HGNC:25965): (leucine rich repeat containing 49) Predicted to be involved in outer dynein arm assembly. Predicted to be located in microtubule. Predicted to be active in cytoplasm. [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=0.2704056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP10	NM_020147.4	c.148C>T	p.Arg50Cys	missense_variant	1/3	ENST00000249861.9
LRRC49	NM_001284357.2	c.19-1459G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP10	ENST00000249861.9	c.148C>T	p.Arg50Cys	missense_variant	1/3	1	NM_020147.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461534 Hom.: 0 Cov.: 65 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 21, 2023

The c.148C>T (p.R50C) alteration is located in exon 1 (coding exon 1) of the THAP10 gene. This alteration results from a C to T substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a cysteine (C). 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	0.76
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Benign	0.75	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.21	B
Vest4		0.33
MutPred		0.74		Loss of MoRF binding (P = 0.1267);
MVP		0.67
MPC		1.3
ClinPred		0.59	D
GERP RS		0.83
Varity_R		0.13
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-71184464;