6-35797242-T-C

Variant names:

• chr6-35797242-T-C
• rs1768391383
• NM_001832.4:c.47A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001252597.2(CLPS):​c.-94A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 43)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLPS NM_001252597.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.800

Genes affected

CLPS (HGNC:2085): (colipase) The protein encoded by this gene is a cofactor needed by pancreatic lipase for efficient dietary lipid hydrolysis. It binds to the C-terminal, non-catalytic domain of lipase, thereby stabilizing an active conformation and considerably increasing the overall hydrophobic binding site. The gene product allows lipase to anchor noncovalently to the surface of lipid micelles, counteracting the destabilizing influence of intestinal bile salts. This cofactor is only expressed in pancreatic acinar cells, suggesting regulation of expression by tissue-specific elements. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12900344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPS	NM_001832.4	c.47A>G	p.Tyr16Cys	missense_variant	Exon 1 of 3	ENST00000259938.7	NP_001823.1
CLPS	NM_001252597.2	c.-94A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4		NP_001239526.1
CLPS	NM_001252598.2	c.47A>G	p.Tyr16Cys	missense_variant	Exon 1 of 2		NP_001239527.1
CLPS	NM_001252597.2	c.-94A>G		5_prime_UTR_variant	Exon 1 of 4		NP_001239526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPS	ENST00000259938.7	c.47A>G	p.Tyr16Cys	missense_variant	Exon 1 of 3	1	NM_001832.4	ENSP00000259938.2
CLPS	ENST00000616014.3	c.47A>G	p.Tyr16Cys	missense_variant	Exon 1 of 2	1		ENSP00000483589.1
LHFPL5	ENST00000651132	c.-370T>C		5_prime_UTR_variant	Exon 1 of 7			ENSP00000498322.1

Frequencies

GnomAD3 genomes Cov.: 43

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 43

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47A>G (p.Y16C) alteration is located in exon 1 (coding exon 1) of the CLPS gene. This alteration results from a A to G substitution at nucleotide position 47, causing the tyrosine (Y) at amino acid position 16 to be replaced by a cysteine (C). 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	0.067
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.71
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.099
Sift	Benign	0.13	T;.
Sift4G	Benign	0.096	T;D
Polyphen		0.0030	B;.
Vest4		0.35
MutPred		0.48		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		0.19
MPC		0.98
ClinPred		0.14	T
GERP RS		-0.23
Varity_R		0.13
gMVP		0.63

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: rs1768391383; hg19: chr6-35765019;