rs121908051

chr16-67944001-G-Achr16-67944001-G-Cchr16-67944001-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.40

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]

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]

ACMG classification

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	UniProt
LCAT	NM_000229.2	c.101C>T	p.Pro34Leu	missense_variant	1/6	ENST00000264005.10
SLC12A4	NM_005072.5	c.*839C>T		3_prime_UTR_variant	24/24	ENST00000316341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCAT	ENST00000264005.10	c.101C>T	p.Pro34Leu	missense_variant	1/6	1	NM_000229.2	P1
SLC12A4	ENST00000316341.8	c.*839C>T		3_prime_UTR_variant	24/24	1	NM_005072.5	P1
LCAT	ENST00000575467.5	c.101C>T	p.Pro34Leu	missense_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000716 AC: 10 AN: 1395980 Hom.: 0 Cov.: 32 AF XY: 0.00000436 AC XY: 3 AN XY: 688330

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.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Norum disease;C0342895:Fish-eye disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 15, 2021

- -

Fish-eye disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.74
MutPred		0.86		Loss of catalytic residue at P33 (P = 0.0191);
MVP		0.97
MPC		1.2
ClinPred		0.96	D
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

Other links and lift over

dbSNP: rs121908051; hg19: chr16-67977904;