chr16-67940050-G-A

Variant names:

• chr16-67940050-G-A
• rs5923
• NM_000229.2:c.1177C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000229.2(LCAT):​c.1177C>T​(p.Leu393Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,613,446 control chromosomes in the GnomAD database, including 2,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (733 hom., cov: 31)
  • Exomes 𝑓: 0.048 (2258 hom.)
• Consequence: LCAT NM_000229.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.231
• Publications: 43 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-67940050-G-A is Benign according to our data. Variant chr16-67940050-G-A is described in ClinVar as Benign. ClinVar VariationId is 320196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	NM_000229.2	MANE Select	c.1177C>T	p.Leu393Leu	synonymous	Exon 6 of 6	NP_000220.1	P04180

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.1177C>T	p.Leu393Leu	synonymous	Exon 6 of 6	ENSP00000264005.5	P04180
	LCAT	ENST00000570369.5	TSL:2	c.179C>T	p.Pro60Leu	missense	Exon 3 of 3	ENSP00000459014.1	I3L1Q6
	LCAT	ENST00000573538.5	TSL:3	n.*498C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000463220.1	J3QKT0

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12185 AN: 152126 Hom.: 729 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0587

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0913

GnomAD2 exomes AF: 0.0484 AC: 12153 AN: 251128 AF XY: 0.0467

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0688

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0493

Gnomad OTH exome AF: 0.0519

GnomAD4 exome AF: 0.0481 AC: 70291 AN: 1461202 Hom.: 2258 Cov.: 31 AF XY: 0.0473 AC XY: 34412 AN XY: 726906

African (AFR) AF: 0.187 AC: 6247 AN: 33480

American (AMR) AF: 0.0373 AC: 1670 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1889 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0288 AC: 2484 AN: 86258

European-Finnish (FIN) AF: 0.0303 AC: 1598 AN: 52746

Middle Eastern (MID) AF: 0.124 AC: 717 AN: 5768

European-Non Finnish (NFE) AF: 0.0470 AC: 52229 AN: 1112002

Other (OTH) AF: 0.0572 AC: 3455 AN: 60388

GnomAD4 genome AF: 0.0802 AC: 12203 AN: 152244 Hom.: 733 Cov.: 31 AF XY: 0.0771 AC XY: 5743 AN XY: 74440

African (AFR) AF: 0.175 AC: 7254 AN: 41536

American (AMR) AF: 0.0586 AC: 896 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5170

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4822

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10614

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.0458 AC: 3112 AN: 68012

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0562 Hom.: 1498

Bravo AF: 0.0845

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0546

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Fish-eye disease (1)
-	-	1	LCAT deficiency (1)
-	-	1	Norum disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.80
PhyloP100		-0.23
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)		0.0		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: rs5923; hg19: chr16-67973953;