NM_198129.4:c.3720-325G>A

Variant names:

• chr18-23845972-G-A
• rs12373237
• NM_198129.4:c.3720-325G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198129.4(LAMA3):​c.3720-325G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 151,980 control chromosomes in the GnomAD database, including 18,964 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (18964 hom., cov: 32)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.3720-325G>A		intron	N/A	NP_937762.2
	LAMA3	NM_001127717.4		c.3720-325G>A		intron	N/A	NP_001121189.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.3720-325G>A		intron	N/A	ENSP00000324532.8
	LAMA3	ENST00000399516.7	TSL:1	c.3720-325G>A		intron	N/A	ENSP00000382432.2
	LAMA3	ENST00000649721.1		c.612-325G>A		intron	N/A	ENSP00000497885.1

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71052 AN: 151862 Hom.: 18966 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.468 AC: 71058 AN: 151980 Hom.: 18964 Cov.: 32 AF XY: 0.459 AC XY: 34132 AN XY: 74288

African (AFR) AF: 0.235 AC: 9729 AN: 41414

American (AMR) AF: 0.446 AC: 6807 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2303 AN: 3466

East Asian (EAS) AF: 0.162 AC: 834 AN: 5160

South Asian (SAS) AF: 0.392 AC: 1883 AN: 4808

European-Finnish (FIN) AF: 0.548 AC: 5794 AN: 10572

Middle Eastern (MID) AF: 0.572 AC: 167 AN: 292

European-Non Finnish (NFE) AF: 0.616 AC: 41870 AN: 67980

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.523 Hom.: 3940

Bravo AF: 0.451

Asia WGS AF: 0.274 AC: 953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.68
DANN	Benign	0.66
PhyloP100		0.050
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: rs12373237; hg19: chr18-21425936;