chr18-23931208-G-C

Variant names:

• chr18-23931208-G-C
• rs1258107
• NM_198129.4:c.8576+7G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198129.4(LAMA3):​c.8576+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,610,772 control chromosomes in the GnomAD database, including 774,639 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70408 hom., cov: 32)
  • Exomes 𝑓: 0.98 (704231 hom.)
• Consequence: LAMA3 NM_198129.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001259
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.524
• Publications: 11 publications found

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

ACMG classification

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-C is Benign according to our data. Variant chr18-23931208-G-C is described in ClinVar as Benign. ClinVar VariationId is 255577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.8576+7G>C		splice_region_variant, intron_variant	Intron 65 of 74	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.3749+7G>C		splice_region_variant, intron_variant	Intron 28 of 37	ENST00000269217.11	NP_000218.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146219 AN: 152176 Hom.: 70356 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.975

GnomAD2 exomes AF: 0.976 AC: 245401 AN: 251424 AF XY: 0.975

Gnomad AFR exome AF: 0.893

Gnomad AMR exome AF: 0.988

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.983

GnomAD4 exome AF: 0.982 AC: 1432907 AN: 1458478 Hom.: 704231 Cov.: 34 AF XY: 0.981 AC XY: 712284 AN XY: 725822

African (AFR) AF: 0.890 AC: 29736 AN: 33408

American (AMR) AF: 0.988 AC: 44188 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 25596 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39688 AN: 39690

South Asian (SAS) AF: 0.936 AC: 80618 AN: 86162

European-Finnish (FIN) AF: 0.995 AC: 53163 AN: 53410

Middle Eastern (MID) AF: 0.967 AC: 5573 AN: 5764

European-Non Finnish (NFE) AF: 0.988 AC: 1095392 AN: 1108938

Other (OTH) AF: 0.978 AC: 58953 AN: 60276

GnomAD4 genome AF: 0.961 AC: 146330 AN: 152294 Hom.: 70408 Cov.: 32 AF XY: 0.961 AC XY: 71554 AN XY: 74454

African (AFR) AF: 0.897 AC: 37266 AN: 41540

American (AMR) AF: 0.978 AC: 14973 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3399 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5184 AN: 5188

South Asian (SAS) AF: 0.933 AC: 4491 AN: 4812

European-Finnish (FIN) AF: 0.995 AC: 10560 AN: 10618

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67210 AN: 68036

Other (OTH) AF: 0.975 AC: 2063 AN: 2116

Alfa AF: 0.979 Hom.: 6537

Bravo AF: 0.961

EpiCase AF: 0.986

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 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

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Junctional epidermolysis bullosa gravis of Herlitz Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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	-0.74
CADD	Benign	0.33
DANN	Benign	0.42
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
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

Other links and lift over

dbSNP: rs1258107; hg19: chr18-21511172;