rs201249971

chr3-185519292-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting

The NM_139248.3(LIPH):c.736T>A(p.Cys246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,098 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00026 ( 6 hom. )

Consequence

LIPH
NM_139248.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.09

Variant links:

Genes affected

LIPH (HGNC:18483): (lipase H) This gene encodes a membrane-bound member of the mammalian triglyceride lipase family. It catalyzes the production of 2-acyl lysophosphatidic acid (LPA), which is a lipid mediator with diverse biological properties that include platelet aggregation, smooth muscle contraction, and stimulation of cell proliferation and motility. [provided by RefSeq, Jul 2008]

LIPH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 3-185519292-A-T is Pathogenic according to our data. Variant chr3-185519292-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000257 (375/1460778) while in subpopulation EAS AF= 0.00879 (349/39692). AF 95% confidence interval is 0.00803. There are 6 homozygotes in gnomad4_exome. There are 192 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LIPH	NM_139248.3 linkuse as main transcript	c.736T>A	p.Cys246Ser	missense_variant	6/10	ENST00000296252.9
LIPH	XM_006713529.5 linkuse as main transcript	c.646T>A	p.Cys216Ser	missense_variant	5/9
LIPH	XM_017005852.3 linkuse as main transcript	c.634T>A	p.Cys212Ser	missense_variant	5/9
LIPH	XM_011512530.4 linkuse as main transcript	c.607T>A	p.Cys203Ser	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LIPH	ENST00000296252.9 linkuse as main transcript	c.736T>A	p.Cys246Ser	missense_variant	6/10	1	NM_139248.3	P1
LIPH	ENST00000424591.6 linkuse as main transcript	c.634T>A	p.Cys212Ser	missense_variant	5/9	1
LIPH	ENST00000452897.1 linkuse as main transcript	c.109T>A	p.Cys37Ser	missense_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251346

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00196

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1460778

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00879

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000125

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00328

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypotrichosis 7

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is predicted to replace cysteine with serine at codon 246 of the LIPH protein, p.(Cys246Ser). The cysteine residue is invariant across species (100 vertebrates, UCSC), and forms a crucial disulphide bond in the lipase domain. There is a large physicochemical difference between cysteine and serine. The variant is present in a large population cohort at a frequency of 0.016% (rs201249971, 39/251,346 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.15% in the East Asian population (36/18,394 alleles). The variant is a Japanese founder variant that has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with autosomal recessive woolly hair/hypotrichosis, and segregates with disease in at least one family (PMID: 19892526, 20213768). Additionally, in vitro functional assays show complete abolition of hydrolytic activity and no ability to activate P2Y5 for the variant (PMID: 20213768). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PS3_Supporting, PP1, PP3. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225403, PMID:19892526). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.956>=0.6). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001552). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hypotrichosis simplex

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2018

The p.Cys246Ser variant in LIPH has been reported in the homozygous or compound heterozygous state in >15 individuals with hypotrichosis and segregated with dis ease in 4 affected relatives from 4 families (Shimomura 2009, Shinkuma 2010, Yos himasu 2011, Tanahashi 2013, Hayashi 2014, Ito 2015). This variant has been desc ribed as a common founder variant in the Japanese population. This variant has b een identified in 0.2% (37/17248) of East Asian chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID: 225403). Although this variant has been seen in the g eneral population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p .Cys246Ser variant may impact protein function (Shinkuma 2010); however, these t ypes of assays may not accurately represent biological function. Computational p rediction tools and conservation analysis suggest that the p.Cys246Ser variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for hypotrichosis in an autosomal recessive manner based upon presenc e in affected individuals, segregation studies, and functional evidence. ACMG/AM P Criteria applied: PM3_VeryStrong, PP1_Moderate, PP3, PS3_Supporting. -

Woolly hair, autosomal recessive 2, with or without hypotrichosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

4.4

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-9.4

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.99

Gain of disorder (P = 0.0081);.;

MVP

0.98

MPC

0.64

ClinPred

1.0

GERP RS

4.0

Varity_R

0.96

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over