Genetic Variant LRRC57:p.Ile81Leu (chr15-42547512-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_153260.3(LRRC57):c.241A>T(p.Ile81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,611,886 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

LRRC57
NM_153260.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.29

Variant links:

Genes affected

LRRC57 (HGNC:26719): (leucine rich repeat containing 57) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

LRRC57 links:

ENSG00000285942 (HGNC:):

ENSG00000285942 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04088846).

BP6

Variant 15-42547512-T-A is Benign according to our data. Variant chr15-42547512-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3291701.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC57	NM_153260.3 link	c.241A>T	p.Ile81Leu	missense_variant	Exon 4 of 6	ENST00000397130.8	NP_694992.2	Q8N9N7A0A024R9M3
LRRC57	XM_047432335.1 link	c.241A>T	p.Ile81Leu	missense_variant	Exon 4 of 6		XP_047288291.1
LRRC57	XM_011521423.4 link	c.241A>T	p.Ile81Leu	missense_variant	Exon 4 of 6		XP_011519725.1
LRRC57	XM_011521424.4 link	c.241A>T	p.Ile81Leu	missense_variant	Exon 4 of 6		XP_011519726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC57	ENST00000397130.8 link	c.241A>T	p.Ile81Leu	missense_variant	Exon 4 of 6	1	NM_153260.3	ENSP00000380319.3		Q8N9N7
ENSG00000285942	ENST00000650210.1 link	n.241A>T		non_coding_transcript_exon_variant	Exon 4 of 9			ENSP00000497618.1		A0A3B3ISV5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152136

Hom.:

Cov.:

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:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000809

AC:

AN:

247328

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134026

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 SAS exome

AF:

0.000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1459632

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

725710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000743

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74462

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:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 06, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.017

T;T;T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.81

.;.;T;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.27

N;N;N;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.14

N;N;N;N

REVEL

Benign

0.092

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;.

Polyphen

0.0

B;B;B;.

Vest4

0.28

MutPred

0.72

Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);

MVP

0.67

MPC

0.32

ClinPred

0.039

GERP RS

2.0

Varity_R

0.056

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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