19-44955448-G-A

Variant names:

• chr19-44955448-G-A
• rs980948842
• NM_001294.4:c.53G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001294.4(CLPTM1):​c.53G>A​(p.Gly18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000524 in 1,334,716 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CLPTM1 NM_001294.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

CLPTM1 (HGNC:2087): (CLPTM1 regulator of GABA type A receptor forward trafficking) Predicted to be involved in regulation of T cell differentiation in thymus. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15918973).
• BS2: High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001294.4. 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
	CLPTM1	NM_001294.4	MANE Select	c.53G>A	p.Gly18Glu	missense	Exon 1 of 14	NP_001285.1	A0A0S2Z3H2
	CLPTM1	NM_001282175.2		c.30+363G>A		intron	N/A	NP_001269104.1	O96005-4
	CLPTM1	NM_001282176.2		c.-235+747G>A		intron	N/A	NP_001269105.1	O96005-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPTM1	ENST00000337392.10	TSL:1 MANE Select	c.53G>A	p.Gly18Glu	missense	Exon 1 of 14	ENSP00000336994.4	O96005-1
	CLPTM1	ENST00000588855.5	TSL:1	n.117+747G>A		intron	N/A
	CLPTM1	ENST00000870268.1		c.53G>A	p.Gly18Glu	missense	Exon 1 of 15	ENSP00000540327.1

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152250 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 13970 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000499 AC: 59 AN: 1182466 Hom.: 0 Cov.: 31 AF XY: 0.0000388 AC XY: 22 AN XY: 567544

African (AFR) AF: 0.00 AC: 0 AN: 23306

American (AMR) AF: 0.00 AC: 0 AN: 10204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15912

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28122

South Asian (SAS) AF: 0.00 AC: 0 AN: 38780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3328

European-Non Finnish (NFE) AF: 0.0000542 AC: 53 AN: 977344

Other (OTH) AF: 0.000103 AC: 5 AN: 48346

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68038

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	CLPTM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.17	N
REVEL	Benign	0.061
Sift	Benign	0.11	T
Sift4G	Uncertain	0.033	D
Polyphen		0.52	P
Vest4		0.31
MutPred		0.22		Gain of solvent accessibility (P = 0.0456)
MVP		0.26
MPC		0.98
ClinPred		0.43	T
GERP RS		2.3
PromoterAI		0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.33
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs980948842; hg19: chr19-45458705;