3-156942645-A-G

Variant names:

• chr3-156942645-A-G
• rs957340843
• NM_001004316.3:c.676A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004316.3(LEKR1):​c.676A>G​(p.Ile226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,119,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I226F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LEKR1 NM_001004316.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10499382).

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.676A>G	p.Ile226Val	missense	Exon 6 of 13	NP_001004316.2	J3KP02

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEKR1	ENST00000356539.9	TSL:5 MANE Select	c.676A>G	p.Ile226Val	missense	Exon 6 of 13	ENSP00000348936.4	J3KP02
	LEKR1	ENST00000470811.6	TSL:2	n.676A>G		non_coding_transcript_exon	Exon 6 of 14	ENSP00000418214.2	A0A8I5FW65
	LEKR1	ENST00000489350.5	TSL:3	n.377A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000268 AC: 3 AN: 1119140 Hom.: 0 Cov.: 28 AF XY: 0.00000364 AC XY: 2 AN XY: 549058

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22706

American (AMR) AF: 0.00 AC: 0 AN: 23008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15466

East Asian (EAS) AF: 0.00 AC: 0 AN: 11838

South Asian (SAS) AF: 0.00 AC: 0 AN: 72394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4348

European-Non Finnish (NFE) AF: 0.00000328 AC: 3 AN: 914548

Other (OTH) AF: 0.00 AC: 0 AN: 40768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.013
Sift	Benign	0.040	D
Sift4G	Benign	0.15	T
Vest4		0.21
MutPred		0.25		Loss of catalytic residue at I226 (P = 0.0474)
MVP		0.13
ClinPred		0.70	D
GERP RS		5.4
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs957340843; hg19: chr3-156660434;