rs3748050

Variant names:

• chr6-35797291-T-C
• rs3748050
• NM_001832.4:c.-3A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001832.4(CLPS):​c.-3A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,563,648 control chromosomes in the GnomAD database, including 22,528 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (1725 hom., cov: 42)
  • Exomes 𝑓: 0.26 (20803 hom.)
• Consequence: CLPS NM_001832.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 13 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPS	NM_001832.4	c.-3A>G		5_prime_UTR_variant	Exon 1 of 3	ENST00000259938.7	NP_001823.1
CLPS	NM_001252597.2	c.-143A>G		5_prime_UTR_variant	Exon 1 of 4		NP_001239526.1
CLPS	NM_001252598.2	c.-3A>G		5_prime_UTR_variant	Exon 1 of 2		NP_001239527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPS	ENST00000259938.7	c.-3A>G		5_prime_UTR_variant	Exon 1 of 3	1	NM_001832.4	ENSP00000259938.2
CLPS	ENST00000616014.3	c.-3A>G		5_prime_UTR_variant	Exon 1 of 2	1		ENSP00000483589.1
LHFPL5	ENST00000651132.1	c.-323+2T>C		splice_donor_variant, intron_variant	Intron 1 of 6			ENSP00000498322.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 37655 AN: 149142 Hom.: 1726 Cov.: 42

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0567

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.246 AC: 60747 AN: 247286 AF XY: 0.246

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.0486

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.256 AC: 362784 AN: 1414388 Hom.: 20803 Cov.: 36 AF XY: 0.256 AC XY: 180398 AN XY: 704644

African (AFR) AF: 0.241 AC: 7567 AN: 31432

American (AMR) AF: 0.250 AC: 11074 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6153 AN: 25142

East Asian (EAS) AF: 0.0414 AC: 1617 AN: 39060

South Asian (SAS) AF: 0.232 AC: 19510 AN: 84016

European-Finnish (FIN) AF: 0.275 AC: 14292 AN: 51950

Middle Eastern (MID) AF: 0.197 AC: 1076 AN: 5474

European-Non Finnish (NFE) AF: 0.267 AC: 287190 AN: 1074600

Other (OTH) AF: 0.245 AC: 14305 AN: 58484

GnomAD4 genome AF: 0.252 AC: 37680 AN: 149260 Hom.: 1725 Cov.: 42 AF XY: 0.249 AC XY: 18172 AN XY: 72968

African (AFR) AF: 0.246 AC: 9920 AN: 40254

American (AMR) AF: 0.237 AC: 3577 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 849 AN: 3418

East Asian (EAS) AF: 0.0560 AC: 286 AN: 5106

South Asian (SAS) AF: 0.232 AC: 1089 AN: 4694

European-Finnish (FIN) AF: 0.282 AC: 2927 AN: 10382

Middle Eastern (MID) AF: 0.198 AC: 57 AN: 288

European-Non Finnish (NFE) AF: 0.272 AC: 18256 AN: 67072

Other (OTH) AF: 0.250 AC: 516 AN: 2060

Alfa AF: 0.268 Hom.: 310

Asia WGS AF: 0.184 AC: 643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.54
PhyloP100		-1.4
PromoterAI		-0.11	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs3748050; hg19: chr6-35765068; COSMIC: COSV52566224; COSMIC: COSV52566224;