Genetic Variant LANCL3:p.Val127Met (chrX-37572249-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001170331.2(LANCL3):c.379G>A(p.Val127Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 112,136 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000052 ( 0 hom. 24 hem. )

Failed GnomAD Quality Control

Consequence

LANCL3
NM_001170331.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

LANCL3 (HGNC:24767): (LanC like family member 3) Predicted to be involved in carbohydrate metabolic process. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LANCL3 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
LANCL3	NM_001170331.2 link	c.379G>A	p.Val127Met	missense_variant	Exon 1 of 5	ENST00000378619.4	NP_001163802.1	Q6ZV70-1
LANCL3	NM_198511.3 link	c.379G>A	p.Val127Met	missense_variant	Exon 1 of 6		NP_940913.1	Q6ZV70-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LANCL3	ENST00000378619.4 link	c.379G>A	p.Val127Met	missense_variant	Exon 1 of 5	1	NM_001170331.2	ENSP00000367882.4	Q6ZV70-1
LANCL3	ENST00000378621.7 link	c.379G>A	p.Val127Met	missense_variant	Exon 1 of 6	1		ENSP00000367885.3	Q6ZV70-2
ENSG00000250349	ENST00000465127.1 link	c.171+146249G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1	B4E171
LANCL3	ENST00000614025.4 link	c.379G>A	p.Val127Met	missense_variant	Exon 1 of 5	2		ENSP00000479231.1	Q6ZV70-2

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112136

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34316

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000944

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

92351

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

29115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000525

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000565

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000522

AC:

AN:

1035096

Hom.:

Cov.:

AF XY:

0.0000722

AC XY:

AN XY:

332422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000354

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:

0.0000627

Gnomad4 OTH exome

AF:

0.0000456

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112136

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000944

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379G>A (p.V127M) alteration is located in exon 1 (coding exon 1) of the LANCL3 gene. This alteration results from a G to A substitution at nucleotide position 379, causing the valine (V) at amino acid position 127 to be replaced by a methionine (M). 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

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.61

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

.;.;T

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.85

T;.;T

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.1

.;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.028

.;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.18

MVP

0.49

MPC

1.0

ClinPred

0.32

GERP RS

4.1

Varity_R

0.21

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over