chr1-51290532-T-A

Position:

• chr1-51290532-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001297663.2(TTC39A):​c.1360A>T​(p.Met454Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: TTC39A NM_001297663.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.449

Genes affected

TTC39A (HGNC:18657): (tetratricopeptide repeat domain 39A) Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052488238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC39A	NM_001297663.2	c.1360A>T	p.Met454Leu	missense_variant	15/18	ENST00000680483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC39A	ENST00000680483.1	c.1360A>T	p.Met454Leu	missense_variant	15/18		NM_001297663.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 12, 2023

The c.1372A>T (p.M458L) alteration is located in exon 15 (coding exon 15) of the TTC39A gene. This alteration results from a A to T substitution at nucleotide position 1372, causing the methionine (M) at amino acid position 458 to be replaced by a leucine (L). 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	Benign	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.73
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.052	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.44	T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;.
Polyphen		0.0, 0.0040	.;B;B;B;.;.
Vest4		0.11
MutPred		0.43		.;Loss of methylation at K486 (P = 0.072);.;.;.;.;
MVP		0.16
MPC		0.34
ClinPred		0.070	T
GERP RS		1.9
Varity_R		0.070
gMVP		0.26

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: rs1467684561; hg19: chr1-51756204;