16-67942417-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000229.2(LCAT):c.694T>A(p.Ser232Thr) variant causes a missense change. The variant allele was found at a frequency of 0.026 in 1,613,908 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S232A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 32)

Exomes 𝑓: 0.027 ( 619 hom. )

Consequence

LCAT
NM_000229.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.82

Publications

51 publications found

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 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

LCAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011052489).

BP6

Variant 16-67942417-A-T is Benign according to our data. Variant chr16-67942417-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 884653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2627/152236) while in subpopulation NFE AF = 0.0287 (1952/67990). AF 95% confidence interval is 0.0276. There are 31 homozygotes in GnomAd4. There are 1221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

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.694T>A	p.Ser232Thr	missense	Exon 5 of 6	NP_000220.1	P04180

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LCAT	ENST00000264005.10	TSL:1 MANE Select	c.694T>A	p.Ser232Thr	missense	Exon 5 of 6	ENSP00000264005.5	P04180
LCAT	ENST00000570980.1	TSL:2	c.478T>A	p.Ser160Thr	missense	Exon 4 of 5	ENSP00000464651.1	J3QSE5
LCAT	ENST00000576450.1	TSL:2	c.160T>A	p.Ser54Thr	missense	Exon 1 of 2	ENSP00000458141.1	I3L0J6

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2628

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00493

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.0175

AC:

4389

AN:

251330

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0289

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0269

AC:

39307

AN:

1461672

Hom.:

619

Cov.:

AF XY:

0.0261

AC XY:

18971

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.00456

AC:

204

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00645

AC:

556

AN:

86258

European-Finnish (FIN)

AF:

0.0270

AC:

1439

AN:

53248

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0321

AC:

35743

AN:

1111984

Other (OTH)

AF:

0.0199

AC:

1204

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2493

4986

7479

9972

12465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1352

2704

4056

5408

6760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

2627

AN:

152236

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1221

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00491

AC:

204

AN:

41538

American (AMR)

AF:

0.00804

AC:

123

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00642

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0271

AC:

287

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0287

AC:

1952

AN:

67990

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

144

289

433

578

722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0220

Hom.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.0291

AC:

108

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00660

AC:

ESP6500EA

AF:

0.0306

AC:

263

ExAC

AF:

0.0180

AC:

2188

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0235

EpiControl

AF:

0.0228

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiovascular phenotype (1)

LCAT deficiency (1)

LCAT-related disorder (1)

Norum disease;C0342895:Fish-eye disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

2.0

PhyloP100

4.8

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.57

Sift

Benign

0.19

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.23

MPC

0.53

ClinPred

0.031

GERP RS

3.8

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.78

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over