19-35249008-G-A

Position:

chr19-35249008-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000621372.4(LSR):c.130G>A(p.Ala44Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,609,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LSR
ENST00000621372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.242

Variant links:

Genes affected

LSR (HGNC:29572): (lipolysis stimulated lipoprotein receptor) Predicted to be involved in several processes, including establishment of skin barrier; protein localization to tricellular tight junction; and tricellular tight junction assembly. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

LSR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.098899275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSR	NM_205834.4 linkuse as main transcript	c.-15G>A		5_prime_UTR_variant	1/10	ENST00000605618.6	NP_991403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSR	ENST00000605618.6 linkuse as main transcript	c.-15G>A		5_prime_UTR_variant	1/10	1	NM_205834.4	ENSP00000474797	A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00000862

AC:

AN:

232000

Hom.:

AF XY:

0.0000157

AC XY:

AN XY:

127540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000301

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:

0.00

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.00000892

AC:

AN:

1456750

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2023

The c.130G>A (p.A44T) alteration is located in exon 1 (coding exon 1) of the LSR gene. This alteration results from a G to A substitution at nucleotide position 130, causing the alanine (A) at amino acid position 44 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 44 of the LSR protein (p.Ala44Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LSR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1911637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

.;T;T;.;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.67

T;T;.;T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.099

T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

L;L;L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.38

.;.;N;N;N;N

REVEL

Benign

0.043

Sift

Uncertain

0.019

.;.;D;T;D;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;T

Polyphen

0.47

P;B;B;.;.;B

Vest4

0.37

MutPred

0.29

Gain of phosphorylation at A44 (P = 0.0083);Gain of phosphorylation at A44 (P = 0.0083);Gain of phosphorylation at A44 (P = 0.0083);Gain of phosphorylation at A44 (P = 0.0083);Gain of phosphorylation at A44 (P = 0.0083);Gain of phosphorylation at A44 (P = 0.0083);

MVP

0.47

MPC

0.23

ClinPred

0.17

GERP RS

-0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.069

gMVP

0.26

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