rs3748051

Variant names:

• chr6-35797166-T-C
• rs3748051
• NM_001832.4:c.84+39A>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.84+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,519,962 control chromosomes in the GnomAD database, including 21,230 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 0.21 (1374 hom., cov: 42)
  • Exomes 𝑓: 0.25 (19856 hom.)
• Consequence: CLPS NM_001832.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 12 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPS	NM_001832.4	c.84+39A>G		intron_variant	Intron 1 of 2	ENST00000259938.7	NP_001823.1
CLPS	NM_001252597.2	c.-57+39A>G		intron_variant	Intron 1 of 3		NP_001239526.1
CLPS	NM_001252598.2	c.84+39A>G		intron_variant	Intron 1 of 1		NP_001239527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPS	ENST00000259938.7	c.84+39A>G		intron_variant	Intron 1 of 2	1	NM_001832.4	ENSP00000259938.2
CLPS	ENST00000616014.3	c.84+39A>G		intron_variant	Intron 1 of 1	1		ENSP00000483589.1
LHFPL5	ENST00000651132.1	c.-446T>C		upstream_gene_variant				ENSP00000498322.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32051 AN: 149312 Hom.: 1374 Cov.: 42

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.0674

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.228 AC: 55647 AN: 243668 AF XY: 0.231

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.249 AC: 340840 AN: 1370526 Hom.: 19856 Cov.: 27 AF XY: 0.248 AC XY: 169894 AN XY: 684420

African (AFR) AF: 0.132 AC: 4092 AN: 31060

American (AMR) AF: 0.233 AC: 10178 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 5763 AN: 24586

East Asian (EAS) AF: 0.0554 AC: 2135 AN: 38554

South Asian (SAS) AF: 0.232 AC: 19122 AN: 82412

European-Finnish (FIN) AF: 0.257 AC: 13271 AN: 51610

Middle Eastern (MID) AF: 0.171 AC: 937 AN: 5468

European-Non Finnish (NFE) AF: 0.263 AC: 272253 AN: 1036252

Other (OTH) AF: 0.230 AC: 13089 AN: 56856

GnomAD4 genome AF: 0.215 AC: 32062 AN: 149436 Hom.: 1374 Cov.: 42 AF XY: 0.212 AC XY: 15522 AN XY: 73048

African (AFR) AF: 0.142 AC: 5735 AN: 40426

American (AMR) AF: 0.217 AC: 3268 AN: 15038

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 784 AN: 3386

East Asian (EAS) AF: 0.0666 AC: 340 AN: 5104

South Asian (SAS) AF: 0.230 AC: 1086 AN: 4732

European-Finnish (FIN) AF: 0.264 AC: 2750 AN: 10422

Middle Eastern (MID) AF: 0.161 AC: 46 AN: 286

European-Non Finnish (NFE) AF: 0.259 AC: 17386 AN: 67094

Other (OTH) AF: 0.211 AC: 435 AN: 2060

Alfa AF: 0.173 Hom.: 163

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.60
PhyloP100		0.070
PromoterAI		0.056	Neutral
Mutation Taster		=100/0	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: rs3748051; hg19: chr6-35764943; COSMIC: COSV52567023; COSMIC: COSV52567023;