Genetic Variant LEKR1:p.Val58Ile (chr3-156852891-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001004316.3(LEKR1):c.172G>A(p.Val58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,534,660 control chromosomes in the GnomAD database, including 1,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.032 ( 117 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1463 hom. )

Consequence

LEKR1
NM_001004316.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.194

Publications

11 publications found

Variant links:

Genes affected

LEKR1 (HGNC:33765): (leucine, glutamate and lysine rich 1)

LEKR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014481544).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4844/152096) while in subpopulation NFE AF = 0.0476 (3232/67920). AF 95% confidence interval is 0.0462. There are 117 homozygotes in GnomAd4. There are 2396 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 117 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEKR1	NM_001004316.3 link	c.172G>A	p.Val58Ile	missense_variant	Exon 3 of 13	ENST00000356539.9	NP_001004316.2	J3KP02
LEKR1	NM_001193283.2 link	c.172G>A	p.Val58Ile	missense_variant	Exon 3 of 5		NP_001180212.1	Q6ZMV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEKR1	ENST00000356539.9 link	c.172G>A	p.Val58Ile	missense_variant	Exon 3 of 13	5	NM_001004316.3	ENSP00000348936.4		J3KP02

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4846

AN:

151978

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00845

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.0764

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0476

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0280

AC:

3965

AN:

141582

AF XY:

0.0275

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0738

Gnomad NFE exome

AF:

0.0468

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0435

AC:

60085

AN:

1382564

Hom.:

1463

Cov.:

AF XY:

0.0421

AC XY:

28750

AN XY:

682328

show subpopulations

African (AFR)

AF:

0.00657

AC:

207

AN:

31508

American (AMR)

AF:

0.0148

AC:

527

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

508

AN:

25126

East Asian (EAS)

AF:

0.0000844

AC:

AN:

35562

South Asian (SAS)

AF:

0.00786

AC:

622

AN:

79150

European-Finnish (FIN)

AF:

0.0691

AC:

2419

AN:

34984

Middle Eastern (MID)

AF:

0.00458

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0498

AC:

53590

AN:

1077062

Other (OTH)

AF:

0.0378

AC:

2183

AN:

57806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2676

5352

8027

10703

13379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2022

4044

6066

8088

10110

<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:

0.0318

AC:

4844

AN:

152096

Hom.:

117

Cov.:

AF XY:

0.0322

AC XY:

2396

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00842

AC:

350

AN:

41544

American (AMR)

AF:

0.0188

AC:

287

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00624

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0764

AC:

808

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0476

AC:

3232

AN:

67920

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

237

475

712

950

1187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0406

Hom.:

349

Bravo

AF:

0.0268

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0483

AC:

186

ESP6500AA

AF:

0.00867

AC:

ESP6500EA

AF:

0.0534

AC:

170

ExAC

AF:

0.0214

AC:

425

Asia WGS

AF:

0.00462

AC:

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

5.2

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.76

T;T;T;.;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T

MetaSVM

Benign

-0.93

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.52

N;N;N;N;.;.

REVEL

Benign

0.12

Sift

Benign

0.31

T;T;T;T;.;.

Sift4G

Benign

0.30

T;T;T;T;T;.

Polyphen

0.021

.;.;.;B;B;.

Vest4

0.095

ClinPred

0.0063

GERP RS

1.6

gMVP

0.0090

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over