chr17-740562-A-T

Variant names:

• chr17-740562-A-T
• NM_024792.3:c.466A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001318007.2(TLCD3A):​c.264A>T​(p.Ter88Cysext*?) variant causes a stop lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TLCD3A NM_001318007.2 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001318007.2 Downstream stopcodon found after 104 codons.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318007.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD3A	NM_024792.3	MANE Select	c.466A>T	p.Ser156Cys	missense	Exon 4 of 5	NP_079068.1	Q8TBR7-2
	TLCD3A	NM_001318007.2		c.264A>T	p.Ter88Cysext*?	stop_lost	Exon 3 of 4	NP_001304936.1
	TLCD3A	NM_001318006.2		c.409-739A>T		intron	N/A	NP_001304935.1	Q8TBR7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD3A	ENST00000308278.13	TSL:1 MANE Select	c.466A>T	p.Ser156Cys	missense	Exon 4 of 5	ENSP00000312017.7	Q8TBR7-2
	TLCD3A	ENST00000301324.8	TSL:1	c.409-739A>T		intron	N/A	ENSP00000301324.8	Q8TBR7-1
	TLCD3A	ENST00000577008.1	TSL:3	c.114A>T	p.Ter38Cysext*?	stop_lost	Exon 2 of 3	ENSP00000460233.2	I3L374

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.90		Gain of helix (P = 0.062)
MVP		0.94
MPC		0.72
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.82
gMVP		0.84

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

Other links and lift over

hg19: chr17-643802;