5-1318433-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030782.5(CLPTM1L):c.1553G>A(p.Arg518His) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CLPTM1L NM_030782.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

CLPTM1L (HGNC:24308): (CLPTM1 like) The protein encoded by this gene is a membrane protein whose overexpression in cisplatin-sensitive cells causes apoptosis. Polymorphisms in this gene have been reported to increase susceptibility to several cancers, including lung, pancreatic, and breast cancers. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29139942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPTM1L	NM_030782.5	c.1553G>A	p.Arg518His	missense_variant	17/17	ENST00000320895.10
CLPTM1L	XM_011514144.3	c.1550G>A	p.Arg517His	missense_variant	17/17
CLPTM1L	XM_024446222.2	c.1019G>A	p.Arg340His	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPTM1L	ENST00000320895.10	c.1553G>A	p.Arg518His	missense_variant	17/17	1	NM_030782.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250612 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461508 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.1553G>A (p.R518H) alteration is located in exon 17 (coding exon 17) of the CLPTM1L gene. This alteration results from a G to A substitution at nucleotide position 1553, causing the arginine (R) at amino acid position 518 to be replaced by a histidine (H). 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	Benign	0.075
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.040	T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.42	N;.;.
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.50	P;P;P
Vest4		0.19
MutPred		0.51		Loss of MoRF binding (P = 0.0906);.;.;
MVP		0.53
MPC		0.48
ClinPred		0.21	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.27

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: rs780423882; hg19: chr5-1318548;