rs1131521

Variant names:

• chr18-23933804-C-T
• rs1131521
• NM_198129.4:c.8731C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198129.4(LAMA3):​c.8731C>T​(p.Leu2911Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,476 control chromosomes in the GnomAD database, including 32,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2284 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30350 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.542
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 18-23933804-C-T is Benign according to our data. Variant chr18-23933804-C-T is described in ClinVar as Benign. ClinVar VariationId is 255578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.542 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.8731C>T	p.Leu2911Leu	synonymous	Exon 67 of 75	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.3904C>T	p.Leu1302Leu	synonymous	Exon 30 of 38	NP_000218.3
	LAMA3	NM_001127717.4		c.8563C>T	p.Leu2855Leu	synonymous	Exon 66 of 74	NP_001121189.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.8731C>T	p.Leu2911Leu	synonymous	Exon 67 of 75	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.3904C>T	p.Leu1302Leu	synonymous	Exon 30 of 38	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.8563C>T	p.Leu2855Leu	synonymous	Exon 66 of 74	ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23694 AN: 152142 Hom.: 2277 Cov.: 33

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.190 AC: 47764 AN: 251310 AF XY: 0.194

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.201 AC: 293494 AN: 1461216 Hom.: 30350 Cov.: 34 AF XY: 0.202 AC XY: 146768 AN XY: 726944

African (AFR) AF: 0.0306 AC: 1023 AN: 33480

American (AMR) AF: 0.174 AC: 7769 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3746 AN: 26136

East Asian (EAS) AF: 0.180 AC: 7142 AN: 39696

South Asian (SAS) AF: 0.238 AC: 20550 AN: 86238

European-Finnish (FIN) AF: 0.238 AC: 12728 AN: 53396

Middle Eastern (MID) AF: 0.133 AC: 762 AN: 5744

European-Non Finnish (NFE) AF: 0.206 AC: 228859 AN: 1111432

Other (OTH) AF: 0.181 AC: 10915 AN: 60376

GnomAD4 genome AF: 0.156 AC: 23709 AN: 152260 Hom.: 2284 Cov.: 33 AF XY: 0.158 AC XY: 11734 AN XY: 74448

African (AFR) AF: 0.0423 AC: 1759 AN: 41552

American (AMR) AF: 0.148 AC: 2264 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3466

East Asian (EAS) AF: 0.168 AC: 868 AN: 5182

South Asian (SAS) AF: 0.237 AC: 1143 AN: 4828

European-Finnish (FIN) AF: 0.249 AC: 2638 AN: 10594

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14107 AN: 68022

Other (OTH) AF: 0.155 AC: 328 AN: 2116

Alfa AF: 0.179 Hom.: 8075

Bravo AF: 0.140

Asia WGS AF: 0.210 AC: 732 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.186

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Junctional epidermolysis bullosa gravis of Herlitz (2)
-	-	2	Laryngo-onycho-cutaneous syndrome (2)
-	-	2	not specified (2)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.3
DANN	Benign	0.82
PhyloP100		0.54
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: rs1131521; hg19: chr18-21513768; COSMIC: COSV52530854; COSMIC: COSV52530854;