18-23901269-C-G

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.6147C>G(p.Ala2049Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,613,664 control chromosomes in the GnomAD database, including 55,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2049A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 3841 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51871 hom. )

Consequence

LAMA3
NM_198129.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.587

Publications

17 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=-0.52).

BP6

Variant 18-23901269-C-G is Benign according to our data. Variant chr18-23901269-C-G is described in ClinVar as Benign. ClinVar VariationId is 255573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.587 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4 link	c.6147C>G	p.Ala2049Ala	synonymous_variant	Exon 48 of 75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6 link	c.1320C>G	p.Ala440Ala	synonymous_variant	Exon 11 of 38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14 link	c.6147C>G	p.Ala2049Ala	synonymous_variant	Exon 48 of 75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11 link	c.1320C>G	p.Ala440Ala	synonymous_variant	Exon 11 of 38	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30705

AN:

152032

Hom.:

3833

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0542

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.237

AC:

59678

AN:

251306

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.233

GnomAD4 exome

AF:

0.262

AC:

382613

AN:

1461514

Hom.:

51871

Cov.:

AF XY:

0.262

AC XY:

190603

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0407

AC:

1361

AN:

33476

American (AMR)

AF:

0.199

AC:

8881

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

4962

AN:

26136

East Asian (EAS)

AF:

0.190

AC:

7547

AN:

39696

South Asian (SAS)

AF:

0.257

AC:

22155

AN:

86246

European-Finnish (FIN)

AF:

0.315

AC:

16835

AN:

53416

Middle Eastern (MID)

AF:

0.162

AC:

931

AN:

5754

European-Non Finnish (NFE)

AF:

0.275

AC:

305755

AN:

1111694

Other (OTH)

AF:

0.235

AC:

14186

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

14867

29734

44602

59469

74336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10144

20288

30432

40576

50720

<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:

0.202

AC:

30716

AN:

152150

Hom.:

3841

Cov.:

AF XY:

0.203

AC XY:

15098

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0540

AC:

2243

AN:

41550

American (AMR)

AF:

0.187

AC:

2866

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

680

AN:

3470

East Asian (EAS)

AF:

0.174

AC:

896

AN:

5162

South Asian (SAS)

AF:

0.253

AC:

1221

AN:

4828

European-Finnish (FIN)

AF:

0.333

AC:

3506

AN:

10544

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18746

AN:

67992

Other (OTH)

AF:

0.198

AC:

418

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1218

2436

3655

4873

6091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.167

Hom.:

487

Bravo

AF:

0.181

Asia WGS

AF:

0.219

AC:

764

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.250

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Mar 03, 2015

GeneDx

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 12, 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 12, 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

-0.52

CADD

Benign

3.7

(source)

DANN

Benign

0.71

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over