NM_000229.2:c.428-23C>A

Variant names:

• chr16-67942789-G-T
• rs13306496
• NM_000229.2:c.428-23C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000229.2(LCAT):​c.428-23C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,612,138 control chromosomes in the GnomAD database, including 1,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (467 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (554 hom.)
• Consequence: LCAT NM_000229.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• fish eye disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• LCAT deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Norum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-67942789-G-T is Benign according to our data. Variant chr16-67942789-G-T is described in ClinVar as Benign. ClinVar VariationId is 1183778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000229.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	NM_000229.2	MANE Select	c.428-23C>A		intron	N/A	NP_000220.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.428-23C>A		intron	N/A	ENSP00000264005.5
	LCAT	ENST00000570980.1	TSL:2	c.212-23C>A		intron	N/A	ENSP00000464651.1
	LCAT	ENST00000570369.5	TSL:2	c.154+72C>A		intron	N/A	ENSP00000459014.1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7100 AN: 152180 Hom.: 463 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00999

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0181 AC: 4497 AN: 248992 AF XY: 0.0165

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00461

Gnomad EAS exome AF: 0.00925

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00931 AC: 13588 AN: 1459840 Hom.: 554 Cov.: 32 AF XY: 0.00939 AC XY: 6822 AN XY: 726290

African (AFR) AF: 0.155 AC: 5184 AN: 33464

American (AMR) AF: 0.0121 AC: 541 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26114

East Asian (EAS) AF: 0.0114 AC: 451 AN: 39688

South Asian (SAS) AF: 0.0306 AC: 2640 AN: 86232

European-Finnish (FIN) AF: 0.000421 AC: 22 AN: 52298

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5766

European-Non Finnish (NFE) AF: 0.00320 AC: 3555 AN: 1111236

Other (OTH) AF: 0.0159 AC: 961 AN: 60334

GnomAD4 genome AF: 0.0467 AC: 7115 AN: 152298 Hom.: 467 Cov.: 33 AF XY: 0.0456 AC XY: 3396 AN XY: 74476

African (AFR) AF: 0.150 AC: 6248 AN: 41548

American (AMR) AF: 0.0227 AC: 347 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5192

South Asian (SAS) AF: 0.0294 AC: 142 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68010

Other (OTH) AF: 0.0327 AC: 69 AN: 2110

Alfa AF: 0.00802 Hom.: 11

Bravo AF: 0.0516

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.85
DANN	Benign	0.67
PhyloP100		1.2
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13306496; hg19: chr16-67976692; COSMIC: COSV50452335; COSMIC: COSV50452335;