NM_198129.4:c.1604-6558A>G

Variant names:

• chr18-23803808-A-G
• rs948435
• NM_198129.4:c.1604-6558A>G

Variant summary

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

The NM_198129.4(LAMA3):​c.1604-6558A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,178 control chromosomes in the GnomAD database, including 48,830 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 0.79 (48830 hom., cov: 32)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.502
• Publications: 3 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.1604-6558A>G		intron_variant	Intron 12 of 74	ENST00000313654.14	NP_937762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.1604-6558A>G		intron_variant	Intron 12 of 74	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000399516.7	c.1604-6558A>G		intron_variant	Intron 12 of 73	1		ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120797 AN: 152060 Hom.: 48774 Cov.: 32

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.803

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

GnomAD4 genome AF: 0.795 AC: 120906 AN: 152178 Hom.: 48830 Cov.: 32 AF XY: 0.793 AC XY: 58971 AN XY: 74384

African (AFR) AF: 0.946 AC: 39322 AN: 41560

American (AMR) AF: 0.811 AC: 12396 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2745 AN: 3468

East Asian (EAS) AF: 0.818 AC: 4230 AN: 5172

South Asian (SAS) AF: 0.733 AC: 3536 AN: 4824

European-Finnish (FIN) AF: 0.666 AC: 7044 AN: 10570

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48887 AN: 67986

Other (OTH) AF: 0.799 AC: 1685 AN: 2110

Alfa AF: 0.770 Hom.: 7703

Bravo AF: 0.816

Asia WGS AF: 0.772 AC: 2685 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.0
DANN	Benign	0.73
PhyloP100		-0.50
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: rs948435; hg19: chr18-21383772;