chr20-36879123-A-T

Variant names:

• chr20-36879123-A-T
• rs754966314
• NM_080628.3:c.272A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080628.3(TLDC2):​c.272A>T​(p.Gln91Leu) 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. 13/21 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: TLDC2 NM_080628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190

Genes affected

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18578869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLDC2	NM_080628.3	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 7	ENST00000217320.8	NP_542195.1
TLDC2	XM_017027674.2	c.-17A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5		XP_016883163.1
TLDC2	NM_001304783.1	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 6		NP_001291712.1
TLDC2	XM_017027674.2	c.-17A>T		5_prime_UTR_variant	Exon 2 of 5		XP_016883163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLDC2	ENST00000217320.8	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 7	1	NM_080628.3	ENSP00000217320.3
TLDC2	ENST00000602922.5	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 6	1		ENSP00000473323.1

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

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272A>T (p.Q91L) alteration is located in exon 3 (coding exon 3) of the TLDC2 gene. This alteration results from a A to T substitution at nucleotide position 272, causing the glutamine (Q) at amino acid position 91 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.0	.;D
REVEL	Benign	0.058
Sift	Uncertain	0.0030	.;D
Sift4G	Benign	0.085	T;T
Polyphen		0.0080	B;B
Vest4		0.31
MutPred		0.56		Loss of disorder (P = 0.074);Loss of disorder (P = 0.074);
MVP		0.13
MPC		0.063
ClinPred		0.52	D
GERP RS		-1.9
Varity_R		0.36
gMVP		0.35

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: rs754966314; hg19: chr20-35507526;