Variant chr9-127455047-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000300417.11(LRSAM1):c.122T>C(p.Leu41Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L41V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRSAM1
ENST00000300417.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Variant links:

Genes affected

LRSAM1 (HGNC:25135): (leucine rich repeat and sterile alpha motif containing 1) This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]

LRSAM1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 linkuse as main transcript	c.122T>C	p.Leu41Pro	missense_variant	4/26	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11 linkuse as main transcript	c.122T>C	p.Leu41Pro	missense_variant	4/26	1	NM_001005373.4	ENSP00000300417	P1	Q6UWE0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727198

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with LRSAM1-related disease. This variant is present in population databases (rs762731732, ExAC 0.003%). This sequence change replaces leucine with proline at codon 41 of the LRSAM1 protein (p.Leu41Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;.;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;T;.;.

M_CAP

Uncertain

0.096

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.5

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.4

D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.98

MutPred

0.88

Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);

MVP

0.89

MPC

0.89

ClinPred

0.99

GERP RS

5.5

Varity_R

0.81

gMVP

0.68

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