3-156920591-A-T

Position:

• chr3-156920591-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004316.3(LEKR1):​c.280A>T​(p.Met94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,313,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: LEKR1 NM_001004316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.933

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058912158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEKR1	NM_001004316.3	c.280A>T	p.Met94Leu	missense_variant	4/13	ENST00000356539.9	NP_001004316.2
LEKR1	NM_001193283.2	c.280A>T	p.Met94Leu	missense_variant	4/5		NP_001180212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEKR1	ENST00000356539.9	c.280A>T	p.Met94Leu	missense_variant	4/13	5	NM_001004316.3	ENSP00000348936	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000762 AC: 10 AN: 1313090 Hom.: 0 Cov.: 24 AF XY: 0.00000461 AC XY: 3 AN XY: 650322

Gnomad4 AFR exome AF: 0.000102

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.78e-7

Gnomad4 OTH exome AF: 0.0000721

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.280A>T (p.M94L) alteration is located in exon 4 (coding exon 3) of the LEKR1 gene. This alteration results from a A to T substitution at nucleotide position 280, causing the methionine (M) at amino acid position 94 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.75
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.47	T;.;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.64	N;N;.
REVEL	Benign	0.020
Sift	Benign	0.52	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.021	.;B;B
Vest4		0.31
MutPred		0.29		Gain of catalytic residue at M94 (P = 0.001);Gain of catalytic residue at M94 (P = 0.001);Gain of catalytic residue at M94 (P = 0.001);
MVP		0.014
ClinPred		0.042	T
GERP RS		3.9
gMVP		0.0059

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs924644718; hg19: chr3-156638380;