Genetic Variant LSR:p.Met1? (chr19-35249023-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_205834.4(LSR):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,453,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

LSR
NM_205834.4 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 67 codons. Genomic position: 35250404. Lost 0.110 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSR	NM_205834.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENST00000605618.6	NP_991403.2	Q86X29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSR	ENST00000605618.6 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	1	NM_205834.4	ENSP00000474797.2		S4R3V8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000179

AC:

AN:

223736

AF XY:

0.0000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000310

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000826

AC:

AN:

1453572

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722558

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33246

American (AMR)

AF:

0.00

AC:

AN:

43294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39438

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00000902

AC:

AN:

1108644

Other (OTH)

AF:

0.00

AC:

AN:

59912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000833

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

.;T;T;.;.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.62

T;T;.;T;T;T;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

L;L;L;L;L;L;.;.

PhyloP100

1.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.98

.;.;N;N;N;N;N;.

REVEL

Benign

0.25

Sift

Uncertain

0.011

.;.;D;D;D;T;D;.

Sift4G

Benign

0.23

T;T;T;T;T;T;D;D

Polyphen

0.81

P;P;P;.;.;P;.;.

Vest4

0.59

MutPred

0.32

Loss of catalytic residue at M49 (P = 0.0974);Loss of catalytic residue at M49 (P = 0.0974);Loss of catalytic residue at M49 (P = 0.0974);Loss of catalytic residue at M49 (P = 0.0974);Loss of catalytic residue at M49 (P = 0.0974);Loss of catalytic residue at M49 (P = 0.0974);.;.;

MVP

0.57

MPC

0.53

ClinPred

0.28

GERP RS

3.7

PromoterAI

-0.39

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.37

gMVP

0.65

Mutation Taster

=17/183

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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19-35249023-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over