Variant rs121908051 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_000229.2(LCAT):c.101C>T(p.Pro34Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000716 in 1,395,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

LCAT
NM_000229.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.40

Variant links:

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

LCAT links:

SLC12A4 (HGNC:10913): (solute carrier family 12 member 4) This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

SLC12A4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 16-67944001-G-A is Pathogenic according to our data. Variant chr16-67944001-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3662.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-67944001-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCAT	NM_000229.2 link	c.101C>T	p.Pro34Leu	missense_variant	1/6	ENST00000264005.10	NP_000220.1	P04180A0A140VK24
SLC12A4	NM_005072.5 link	c.*839C>T		3_prime_UTR_variant	24/24	ENST00000316341.8	NP_005063.1	Q9UP95-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LCAT	ENST00000264005.10 link	c.101C>T	p.Pro34Leu	missense_variant	1/6	1	NM_000229.2	ENSP00000264005.5	P04180
SLC12A4	ENST00000316341 link	c.*839C>T		3_prime_UTR_variant	24/24	1	NM_005072.5	ENSP00000318557.3	Q9UP95-1
LCAT	ENST00000575467.5 link	n.101C>T		non_coding_transcript_exon_variant	1/6	5		ENSP00000460653.1	I3L3R0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000716

AC:

AN:

1395980

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

688330

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000650

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fish-eye disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 1992

- -

Norum disease;C0342895:Fish-eye disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0040

Polyphen

0.95

Vest4

0.74

MutPred

0.86

Loss of catalytic residue at P33 (P = 0.0191);

MVP

0.97

MPC

1.2

ClinPred

0.96

GERP RS

5.1

Varity_R

0.27

gMVP

0.76

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