rs1131521

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198129.4(LAMA3):c.8731C>T(p.Leu2911Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,476 control chromosomes in the GnomAD database, including 32,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2284 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30350 hom. )

Consequence

LAMA3
NM_198129.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.542

Publications

19 publications found

Variant links:

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

LAMA3 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
laryngo-onycho-cutaneous syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 18-23933804-C-T is Benign according to our data. Variant chr18-23933804-C-T is described in ClinVar as Benign. ClinVar VariationId is 255578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.542 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4 link	c.8731C>T	p.Leu2911Leu	synonymous_variant	Exon 67 of 75	ENST00000313654.14	NP_937762.2	Q16787-2
LAMA3	NM_000227.6 link	c.3904C>T	p.Leu1302Leu	synonymous_variant	Exon 30 of 38	ENST00000269217.11	NP_000218.3	Q16787-1A0A0A6YYF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14 link	c.8731C>T	p.Leu2911Leu	synonymous_variant	Exon 67 of 75	1	NM_198129.4	ENSP00000324532.8		Q16787-2
LAMA3	ENST00000269217.11 link	c.3904C>T	p.Leu1302Leu	synonymous_variant	Exon 30 of 38	1	NM_000227.6	ENSP00000269217.5		Q16787-1A0A0A6YYF2

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23694

AN:

152142

Hom.:

2277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0425

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.190

AC:

47764

AN:

251310

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.174

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.183

GnomAD4 exome

AF:

0.201

AC:

293494

AN:

1461216

Hom.:

30350

Cov.:

AF XY:

0.202

AC XY:

146768

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.0306

AC:

1023

AN:

33480

American (AMR)

AF:

0.174

AC:

7769

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

3746

AN:

26136

East Asian (EAS)

AF:

0.180

AC:

7142

AN:

39696

South Asian (SAS)

AF:

0.238

AC:

20550

AN:

86238

European-Finnish (FIN)

AF:

0.238

AC:

12728

AN:

53396

Middle Eastern (MID)

AF:

0.133

AC:

762

AN:

5744

European-Non Finnish (NFE)

AF:

0.206

AC:

228859

AN:

1111432

Other (OTH)

AF:

0.181

AC:

10915

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

12739

25479

38218

50958

63697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7982

15964

23946

31928

39910

<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:

0.156

AC:

23709

AN:

152260

Hom.:

2284

Cov.:

AF XY:

0.158

AC XY:

11734

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0423

AC:

1759

AN:

41552

American (AMR)

AF:

0.148

AC:

2264

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

499

AN:

3466

East Asian (EAS)

AF:

0.168

AC:

868

AN:

5182

South Asian (SAS)

AF:

0.237

AC:

1143

AN:

4828

European-Finnish (FIN)

AF:

0.249

AC:

2638

AN:

10594

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14107

AN:

68022

Other (OTH)

AF:

0.155

AC:

328

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1004

2007

3011

4014

5018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.179

Hom.:

8075

Bravo

AF:

0.140

Asia WGS

AF:

0.210

AC:

732

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.186

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laryngo-onycho-cutaneous syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.3

(source)

DANN

Benign

0.82

PhyloP100

0.54

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

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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