9-127479887-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005373.4(LRSAM1):c.952A>G(p.Asn318Asp) variant causes a missense change. The variant allele was found at a frequency of 0.776 in 1,613,908 control chromosomes in the GnomAD database, including 488,141 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N318H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 43334 hom., cov: 33)

Exomes 𝑓: 0.78 ( 444807 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.07

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2P
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

LRSAM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.8612993E-7).

BP6

Variant 9-127479887-A-G is Benign according to our data. Variant chr9-127479887-A-G is described in ClinVar as Benign. ClinVar VariationId is 365021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRSAM1	NM_001005373.4	MANE Select	c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	NP_001005373.1	Q6UWE0-1
LRSAM1	NM_001005374.4		c.952A>G	p.Asn318Asp	missense	Exon 13 of 25	NP_001005374.1	Q6UWE0-1
LRSAM1	NM_001384142.1		c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	NP_001371071.1	Q6UWE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	ENSP00000300417.6	Q6UWE0-1
LRSAM1	ENST00000373322.1	TSL:1	c.952A>G	p.Asn318Asp	missense	Exon 13 of 25	ENSP00000362419.1	Q6UWE0-1
LRSAM1	ENST00000870574.1		c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes

AF:

0.752

AC:

114292

AN:

152046

Hom.:

43298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.782

Gnomad ASJ

AF:

0.658

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.767

Gnomad FIN

AF:

0.872

Gnomad MID

AF:

0.726

Gnomad NFE

AF:

0.787

Gnomad OTH

AF:

0.739

GnomAD2 exomes

AF:

0.780

AC:

195492

AN:

250724

AF XY:

0.778

show subpopulations

Gnomad AFR exome

AF:

0.673

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.659

Gnomad EAS exome

AF:

0.682

Gnomad FIN exome

AF:

0.874

Gnomad NFE exome

AF:

0.783

Gnomad OTH exome

AF:

0.770

GnomAD4 exome

AF:

0.779

AC:

1138322

AN:

1461744

Hom.:

444807

Cov.:

AF XY:

0.778

AC XY:

565956

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.674

AC:

22565

AN:

33480

American (AMR)

AF:

0.850

AC:

38028

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

17086

AN:

26134

East Asian (EAS)

AF:

0.694

AC:

27549

AN:

39692

South Asian (SAS)

AF:

0.773

AC:

66687

AN:

86252

European-Finnish (FIN)

AF:

0.874

AC:

46638

AN:

53350

Middle Eastern (MID)

AF:

0.698

AC:

4025

AN:

5768

European-Non Finnish (NFE)

AF:

0.783

AC:

870137

AN:

1111956

Other (OTH)

AF:

0.755

AC:

45607

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

15355

30709

46064

61418

76773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20604

41208

61812

82416

103020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.752

AC:

114383

AN:

152164

Hom.:

43334

Cov.:

AF XY:

0.755

AC XY:

56151

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.670

AC:

27786

AN:

41488

American (AMR)

AF:

0.782

AC:

11965

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.658

AC:

2284

AN:

3472

East Asian (EAS)

AF:

0.681

AC:

3507

AN:

5152

South Asian (SAS)

AF:

0.767

AC:

3701

AN:

4828

European-Finnish (FIN)

AF:

0.872

AC:

9248

AN:

10600

Middle Eastern (MID)

AF:

0.736

AC:

215

AN:

292

European-Non Finnish (NFE)

AF:

0.787

AC:

53494

AN:

68008

Other (OTH)

AF:

0.737

AC:

1558

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1473

2945

4418

5890

7363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.769

Hom.:

193711

Bravo

AF:

0.742

TwinsUK

AF:

0.775

AC:

2874

ALSPAC

AF:

0.776

AC:

2991

ESP6500AA

AF:

0.682

AC:

3003

ESP6500EA

AF:

0.773

AC:

6642

ExAC

AF:

0.777

AC:

94310

Asia WGS

AF:

0.720

AC:

2506

AN:

3476

EpiCase

AF:

0.761

EpiControl

AF:

0.767

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease axonal type 2P (5)

not provided (2)

Charcot-Marie-Tooth disease (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.028

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.13

MetaRNN

Benign

7.9e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.0

PhyloP100

4.1

PrimateAI

Benign

0.37

PROVEAN

Benign

1.7

REVEL

Benign

0.15

Sift

Benign

0.77

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.032

MPC

0.19

ClinPred

0.0098

GERP RS

5.9

Varity_R

0.076

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over