17-737891-G-C

Variant names:

• chr17-737891-G-C
• rs143392294
• NM_024792.3:c.252G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024792.3(TLCD3A):​c.252G>C​(p.Met84Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M84T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TLCD3A NM_024792.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34

Genes affected

TLCD3A (HGNC:29646): (TLC domain containing 3A) The protein encoded by this gene is a membrane-associated protein that promotes lung carcinogenesis. The encoded protein may be involved in amino acid transport and glutathione metabolism since it can interact with a solute carrier family member (SLC3A2) and an isoform of gamma-glutamyltranspeptidase-like 3. An alternatively spliced variant encoding a protein that lacks a 32 aa internal segment showed the opposite effect, inhibiting lung cancer cell growth. Knockdown of this gene also inhibited lung carcinogenesis and tumor cell growth. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD3A	NM_024792.3	c.252G>C	p.Met84Ile	missense_variant	Exon 3 of 5	ENST00000308278.13	NP_079068.1
TLCD3A	NM_001318006.2	c.252G>C	p.Met84Ile	missense_variant	Exon 3 of 4		NP_001304935.1
TLCD3A	NM_001318007.2	c.207-2614G>C		intron_variant	Intron 2 of 3		NP_001304936.1
TLCD3A	NM_001318008.2	c.207-3410G>C		intron_variant	Intron 2 of 2		NP_001304937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD3A	ENST00000308278.13	c.252G>C	p.Met84Ile	missense_variant	Exon 3 of 5	1	NM_024792.3	ENSP00000312017.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.092	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.67	P;D
Vest4		0.87
MutPred		0.56		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.76
MPC		0.50
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.70

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: rs143392294; hg19: chr17-641131;