rs62273959

Variant names:

• chr3-156852891-G-A
• rs62273959
• NM_001004316.3:c.172G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.194
• Publications: 11 publications found

Genes affected

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004316.3. 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
	LEKR1	NM_001004316.3	MANE Select	c.172G>A	p.Val58Ile	missense	Exon 3 of 13	NP_001004316.2	J3KP02
	LEKR1	NM_001193283.2		c.172G>A	p.Val58Ile	missense	Exon 3 of 5	NP_001180212.1	Q6ZMV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEKR1	ENST00000356539.9	TSL:5 MANE Select	c.172G>A	p.Val58Ile	missense	Exon 3 of 13	ENSP00000348936.4	J3KP02
	LEKR1	ENST00000491763.1	TSL:1	c.172G>A	p.Val58Ile	missense	Exon 3 of 5	ENSP00000474182.1	Q6ZMV7
	LEKR1	ENST00000477399.5	TSL:2	c.172G>A	p.Val58Ile	missense	Exon 3 of 5	ENSP00000425282.1	Q6ZMV7

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4846 AN: 151978 Hom.: 117 Cov.: 32

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

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.: 30 AF XY: 0.0421 AC XY: 28750 AN XY: 682328

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: 3 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: 26 AN: 5682

European-Non Finnish (NFE) AF: 0.0498 AC: 53590 AN: 1077062

Other (OTH) AF: 0.0378 AC: 2183 AN: 57806

GnomAD4 genome AF: 0.0318 AC: 4844 AN: 152096 Hom.: 117 Cov.: 32 AF XY: 0.0322 AC XY: 2396 AN XY: 74340

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: 85 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00624 AC: 30 AN: 4810

European-Finnish (FIN) AF: 0.0764 AC: 808 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0476 AC: 3232 AN: 67920

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

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: 12

ESP6500EA AF: 0.0534 AC: 170

ExAC AF: 0.0214 AC: 425

Asia WGS AF: 0.00462 AC: 16 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.2
DANN	Uncertain	0.98
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.12
Sift	Benign	0.31	T
Sift4G	Benign	0.30	T
Polyphen		0.021	B
Vest4		0.095
ClinPred		0.0063	T
GERP RS		1.6
gMVP		0.0090
Mutation Taster		=96/4	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: rs62273959; hg19: chr3-156570680; COSMIC: COSV62963715; COSMIC: COSV62963715;