rs763863588

Variant names:

• chr17-738021-C-T
• rs763863588
• NM_024792.3:c.382C>T

Variant summary

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

The NM_024792.3(TLCD3A):​c.382C>T​(p.Leu128Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TLCD3A NM_024792.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD3A	NM_024792.3	c.382C>T	p.Leu128Phe	missense_variant	Exon 3 of 5	ENST00000308278.13	NP_079068.1
TLCD3A	NM_001318006.2	c.382C>T	p.Leu128Phe	missense_variant	Exon 3 of 4		NP_001304935.1
TLCD3A	NM_001318007.2	c.207-2484C>T		intron_variant	Intron 2 of 3		NP_001304936.1
TLCD3A	NM_001318008.2	c.207-3280C>T		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.382C>T	p.Leu128Phe	missense_variant	Exon 3 of 5	1	NM_024792.3	ENSP00000312017.7

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151558 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251472 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456996 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724808

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151558 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73980

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382C>T (p.L128F) alteration is located in exon 3 (coding exon 3) of the FAM57A gene. This alteration results from a C to T substitution at nucleotide position 382, causing the leucine (L) at amino acid position 128 to be replaced by a phenylalanine (F). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Uncertain	0.61
Sift	Benign	0.052	T;D
Sift4G	Benign	0.064	T;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.49		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.67
MPC		0.76
ClinPred		0.75	D
GERP RS		2.7
Varity_R		0.23
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763863588; hg19: chr17-641261;