20-62318579-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005560.6(LAMA5):c.7114G>A(p.Asp2372Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,610,634 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 6 hom., cov: 30)

Exomes 𝑓: 0.0076 ( 50 hom. )

Consequence

LAMA5
NM_005560.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.462

Publications

7 publications found

Variant links:

Genes affected

LAMA5 (HGNC:6485): (laminin subunit alpha 5) This gene encodes one of the vertebrate laminin alpha chains. Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. The protein encoded by this gene is the alpha-5 subunit of of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523). [provided by RefSeq, Jun 2013]

LAMA5 Gene-Disease associations (from GenCC):

nephrotic syndrome, IIa 26
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
LAMA5-related multisystemic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LAMA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033178926).

BP6

Variant 20-62318579-C-T is Benign according to our data. Variant chr20-62318579-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438606.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00583 (885/151816) while in subpopulation NFE AF = 0.00842 (572/67898). AF 95% confidence interval is 0.00785. There are 6 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA5	NM_005560.6 link	c.7114G>A	p.Asp2372Asn	missense_variant	Exon 53 of 80	ENST00000252999.7	NP_005551.3	O15230-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA5	ENST00000252999.7 link	c.7114G>A	p.Asp2372Asn	missense_variant	Exon 53 of 80	1	NM_005560.6	ENSP00000252999.3		O15230-1
LAMA5	ENST00000481120.1 link	n.342G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

883

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00447

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00972

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00842

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00684

AC:

1692

AN:

247502

AF XY:

0.00697

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.00972

Gnomad OTH exome

AF:

0.00679

GnomAD4 exome

AF:

0.00756

AC:

11027

AN:

1458818

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

5459

AN XY:

725742

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33468

American (AMR)

AF:

0.00356

AC:

159

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.0154

AC:

402

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00234

AC:

202

AN:

86240

European-Finnish (FIN)

AF:

0.0102

AC:

526

AN:

51488

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00832

AC:

9244

AN:

1111156

Other (OTH)

AF:

0.00675

AC:

407

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

643

1286

1929

2572

3215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00583

AC:

885

AN:

151816

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

425

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

41390

American (AMR)

AF:

0.00446

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00332

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00972

AC:

103

AN:

10600

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00842

AC:

572

AN:

67898

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00229

AC:

ESP6500EA

AF:

0.00924

AC:

ExAC

AF:

0.00685

AC:

824

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMA5: BS2 -

Polymicrogyria

Uncertain:1

Sep 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

this variant was indentified in an individual with malformations of cortical development -

LAMA5-related disorder

Benign:1

Nov 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.0

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.026

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.5

PhyloP100

0.46

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

REVEL

Benign

0.053

Sift

Benign

0.13

Sift4G

Benign

0.11

Polyphen

0.26

Vest4

0.17

MVP

0.33

ClinPred

0.0078

GERP RS

2.9

Varity_R

0.044

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(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

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20-62318579-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over