NM_198129.4:c.6201+53A>G

Variant names:

• chr18-23901376-A-G
• rs1154227
• NM_198129.4:c.6201+53A>G

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.6201+53A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,451,370 control chromosomes in the GnomAD database, including 106,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10584 hom., cov: 32)
  • Exomes 𝑓: 0.38 (96230 hom.)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.623
• 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=-0.79).
• BP6: Variant 18-23901376-A-G is Benign according to our data. Variant chr18-23901376-A-G is described in ClinVar as Benign. ClinVar VariationId is 1184664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.6201+53A>G		intron_variant	Intron 48 of 74	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.1374+53A>G		intron_variant	Intron 11 of 37	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.6201+53A>G		intron_variant	Intron 48 of 74	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11	c.1374+53A>G		intron_variant	Intron 11 of 37	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55262 AN: 151890 Hom.: 10578 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.377

GnomAD4 exome AF: 0.375 AC: 487328 AN: 1299362 Hom.: 96230 AF XY: 0.378 AC XY: 247111 AN XY: 654478

African (AFR) AF: 0.304 AC: 9242 AN: 30434

American (AMR) AF: 0.360 AC: 15863 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7739 AN: 25162

East Asian (EAS) AF: 0.791 AC: 30773 AN: 38882

South Asian (SAS) AF: 0.451 AC: 37038 AN: 82206

European-Finnish (FIN) AF: 0.408 AC: 21543 AN: 52850

Middle Eastern (MID) AF: 0.371 AC: 1507 AN: 4058

European-Non Finnish (NFE) AF: 0.355 AC: 343051 AN: 966846

Other (OTH) AF: 0.375 AC: 20572 AN: 54842

GnomAD4 genome AF: 0.364 AC: 55288 AN: 152008 Hom.: 10584 Cov.: 32 AF XY: 0.371 AC XY: 27531 AN XY: 74296

African (AFR) AF: 0.307 AC: 12728 AN: 41484

American (AMR) AF: 0.344 AC: 5249 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1084 AN: 3462

East Asian (EAS) AF: 0.771 AC: 3971 AN: 5152

South Asian (SAS) AF: 0.459 AC: 2212 AN: 4818

European-Finnish (FIN) AF: 0.424 AC: 4479 AN: 10556

Middle Eastern (MID) AF: 0.337 AC: 97 AN: 288

European-Non Finnish (NFE) AF: 0.360 AC: 24470 AN: 67948

Other (OTH) AF: 0.382 AC: 807 AN: 2114

Alfa AF: 0.343 Hom.: 31122

Bravo AF: 0.355

Asia WGS AF: 0.590 AC: 2052 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

- -

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

- -

Laryngo-onycho-cutaneous syndrome Benign:1

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: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	-0.79
CADD	Benign	1.3
DANN	Benign	0.78
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1154227; hg19: chr18-21481340;