17-732711-G-C

Variant names:

• chr17-732711-G-C
• rs773825578
• NM_024792.3:c.64G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024792.3(TLCD3A):​c.64G>C​(p.Ala22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,440,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: TLCD3A NM_024792.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0260

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052179307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD3A	NM_024792.3	c.64G>C	p.Ala22Pro	missense_variant	Exon 1 of 5	ENST00000308278.13	NP_079068.1
TLCD3A	NM_001318006.2	c.64G>C	p.Ala22Pro	missense_variant	Exon 1 of 4		NP_001304935.1
TLCD3A	NM_001318007.2	c.64G>C	p.Ala22Pro	missense_variant	Exon 1 of 4		NP_001304936.1
TLCD3A	NM_001318008.2	c.64G>C	p.Ala22Pro	missense_variant	Exon 1 of 3		NP_001304937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD3A	ENST00000308278.13	c.64G>C	p.Ala22Pro	missense_variant	Exon 1 of 5	1	NM_024792.3	ENSP00000312017.7

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151846 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00175

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000405 AC: 3 AN: 74102 Hom.: 0 AF XY: 0.0000235 AC XY: 1 AN XY: 42626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000792

Gnomad SAS exome AF: 0.0000617

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000473 AC: 61 AN: 1288952 Hom.: 1 Cov.: 31 AF XY: 0.0000410 AC XY: 26 AN XY: 634692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.0000576

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000379

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151952 Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000315 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64G>C (p.A22P) alteration is located in exon 1 (coding exon 1) of the FAM57A gene. This alteration results from a G to C substitution at nucleotide position 64, causing the alanine (A) at amino acid position 22 to be replaced by a proline (P). 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	0.48
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.22	T;.;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.38	B;.;P
Vest4		0.26
MutPred		0.57		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.11
MPC		0.44
ClinPred		0.040	T
GERP RS		0.54
Varity_R		0.16
gMVP		0.59

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: rs773825578; hg19: chr17-635951;