17-741347-C-G

Variant names:

• chr17-741347-C-G
• rs753871349
• NM_024792.3:c.551C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024792.3(TLCD3A):​c.551C>G​(p.Thr184Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T184M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLCD3A NM_024792.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024792.3. 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.551C>G	p.Thr184Arg	missense	Exon 5 of 5	NP_079068.1	Q8TBR7-2
	TLCD3A	NM_001318006.2		c.455C>G	p.Thr152Arg	missense	Exon 4 of 4	NP_001304935.1	Q8TBR7-1
	TLCD3A	NM_001318007.2		c.*85C>G		3_prime_UTR	Exon 4 of 4	NP_001304936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLCD3A	ENST00000308278.13	TSL:1 MANE Select	c.551C>G	p.Thr184Arg	missense	Exon 5 of 5	ENSP00000312017.7	Q8TBR7-2
	TLCD3A	ENST00000301324.8	TSL:1	c.455C>G	p.Thr152Arg	missense	Exon 4 of 4	ENSP00000301324.8	Q8TBR7-1
	TLCD3A	ENST00000572018.5	TSL:3	c.*43C>G		3_prime_UTR	Exon 3 of 3	ENSP00000460150.1	I3L336

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.84		Gain of methylation at T184 (P = 0.0234)
MVP		0.85
MPC		0.78
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.86
Mutation Taster		=79/21	polymorphism

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

dbSNP: rs753871349; hg19: chr17-644587;