rs1768391383

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

LHFPL5 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 67

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252597.2. 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
	CLPS	NM_001832.4	MANE Select	c.47A>G	p.Tyr16Cys	missense	Exon 1 of 3	NP_001823.1	P04118
	CLPS	NM_001252597.2		c.-94A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001239526.1	A0A087WZW1
	CLPS	NM_001252598.2		c.47A>G	p.Tyr16Cys	missense	Exon 1 of 2	NP_001239527.1	A0A087X0Q7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPS	ENST00000259938.7	TSL:1 MANE Select	c.47A>G	p.Tyr16Cys	missense	Exon 1 of 3	ENSP00000259938.2	P04118
	CLPS	ENST00000616014.3	TSL:1	c.47A>G	p.Tyr16Cys	missense	Exon 1 of 2	ENSP00000483589.1	A0A087X0Q7
	CLPS	ENST00000912425.1		c.47A>G	p.Tyr16Cys	missense	Exon 2 of 4	ENSP00000582484.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 43

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.80
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.099
Sift	Benign	0.13	T
Sift4G	Benign	0.096	T
Polyphen		0.0030	B
Vest4		0.35
MutPred		0.48		Loss of helix (P = 0.2271)
MVP		0.19
MPC		0.98
ClinPred		0.14	T
GERP RS		-0.23
PromoterAI		0.0042	Neutral
Varity_R		0.13
gMVP		0.63
Mutation Taster		=98/2	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: rs1768391383; hg19: chr6-35765019;