18-23931208-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198129.4(LAMA3):c.8576+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,610,880 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 10 hom. )

Consequence

LAMA3
NM_198129.4 splice_region, intron

Scores

Splicing: ADA: 0.00002224

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.524

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 18-23931208-G-T is Benign according to our data. Variant chr18-23931208-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 326334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00236 (360/152308) while in subpopulation NFE AF = 0.004 (272/68038). AF 95% confidence interval is 0.00361. There are 1 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4 link	c.8576+7G>T		splice_region_variant, intron_variant	Intron 65 of 74	ENST00000313654.14	NP_937762.2	Q16787-2
LAMA3	NM_000227.6 link	c.3749+7G>T		splice_region_variant, intron_variant	Intron 28 of 37	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.8576+7G>T		splice_region_variant, intron_variant	Intron 65 of 74	1	NM_198129.4	ENSP00000324532.8		Q16787-2
LAMA3	ENST00000269217.11 link	c.3749+7G>T		splice_region_variant, intron_variant	Intron 28 of 37	1	NM_000227.6	ENSP00000269217.5		Q16787-1A0A0A6YYF2

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

360

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00243

AC:

612

AN:

251424

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00404

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00349

AC:

5089

AN:

1458572

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

2458

AN XY:

725886

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33432

American (AMR)

AF:

0.00110

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00471

AC:

123

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.000499

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00167

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00415

AC:

4606

AN:

1108984

Other (OTH)

AF:

0.00255

AC:

154

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00236

AC:

360

AN:

152308

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

166

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41546

American (AMR)

AF:

0.00137

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00400

AC:

272

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00368

Hom.:

6537

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laryngo-onycho-cutaneous syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.74

CADD

Benign

0.31

(source)

DANN

Benign

0.41

PhyloP100

-0.52

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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