3-156992712-C-T

Position:

• chr3-156992712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001004316.3(LEKR1):​c.887C>T​(p.Ser296Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 879,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: LEKR1 NM_001004316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEKR1	NM_001004316.3	c.887C>T	p.Ser296Phe	missense_variant	8/13	ENST00000356539.9	NP_001004316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEKR1	ENST00000356539.9	c.887C>T	p.Ser296Phe	missense_variant	8/13	5	NM_001004316.3	ENSP00000348936.4
LEKR1	ENST00000470811.6	n.*365C>T		non_coding_transcript_exon_variant	9/14	2		ENSP00000418214.2
LEKR1	ENST00000470811.6	n.*365C>T		3_prime_UTR_variant	9/14	2		ENSP00000418214.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000455 AC: 4 AN: 879344 Hom.: 0 Cov.: 12 AF XY: 0.00000232 AC XY: 1 AN XY: 431228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000400

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 29, 2021

The c.887C>T (p.S296F) alteration is located in exon 8 (coding exon 7) of the LEKR1 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the serine (S) at amino acid position 296 to be replaced by a phenylalanine (F). 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	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.032
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.048	D
Vest4		0.25
MutPred		0.29		Loss of phosphorylation at S296 (P = 0.0252);
MVP		0.32
ClinPred		0.91	D
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1731233957; hg19: chr3-156710501; COSMIC: COSV104667348; COSMIC: COSV104667348;