rs2241643

Variant names:

• chr18-23949758-G-A
• rs2241643
• NM_198129.4:c.9352-7G>A

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.9352-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,612,626 control chromosomes in the GnomAD database, including 319,876 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 0.51 (22825 hom., cov: 30)
  • Exomes 𝑓: 0.62 (297051 hom.)
• Consequence: LAMA3 NM_198129.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005356
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.989
• Publications: 17 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=-0.78).
• BP6: Variant 18-23949758-G-A is Benign according to our data. Variant chr18-23949758-G-A is described in ClinVar as Benign. ClinVar VariationId is 255580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 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.9352-7G>A		splice_region intron	N/A	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.4525-7G>A		splice_region intron	N/A	NP_000218.3
	LAMA3	NM_001127717.4		c.9184-7G>A		splice_region 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.9352-7G>A		splice_region intron	N/A	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.4525-7G>A		splice_region intron	N/A	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.9184-7G>A		splice_region intron	N/A	ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.514 AC: 77894 AN: 151606 Hom.: 22827 Cov.: 30

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.535 AC: 134519 AN: 251304 AF XY: 0.547

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.624 AC: 911763 AN: 1460902 Hom.: 297051 Cov.: 44 AF XY: 0.622 AC XY: 451801 AN XY: 726762

African (AFR) AF: 0.247 AC: 8254 AN: 33464

American (AMR) AF: 0.387 AC: 17324 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 18261 AN: 26126

East Asian (EAS) AF: 0.138 AC: 5478 AN: 39696

South Asian (SAS) AF: 0.430 AC: 37112 AN: 86218

European-Finnish (FIN) AF: 0.640 AC: 34181 AN: 53406

Middle Eastern (MID) AF: 0.605 AC: 3387 AN: 5596

European-Non Finnish (NFE) AF: 0.676 AC: 751580 AN: 1111336

Other (OTH) AF: 0.600 AC: 36186 AN: 60342

GnomAD4 genome AF: 0.513 AC: 77900 AN: 151724 Hom.: 22825 Cov.: 30 AF XY: 0.505 AC XY: 37473 AN XY: 74148

African (AFR) AF: 0.260 AC: 10763 AN: 41334

American (AMR) AF: 0.484 AC: 7368 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2441 AN: 3464

East Asian (EAS) AF: 0.162 AC: 835 AN: 5142

South Asian (SAS) AF: 0.415 AC: 1993 AN: 4798

European-Finnish (FIN) AF: 0.636 AC: 6678 AN: 10502

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.675 AC: 45853 AN: 67932

Other (OTH) AF: 0.545 AC: 1151 AN: 2110

Alfa AF: 0.626 Hom.: 49177

Bravo AF: 0.492

Asia WGS AF: 0.288 AC: 1002 AN: 3478

EpiCase AF: 0.688

EpiControl AF: 0.686

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	-0.78
CADD	Benign	0.95
DANN	Benign	0.47
PhyloP100		-0.99
PromoterAI		-0.0010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.016
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: rs2241643; hg19: chr18-21529722; COSMIC: COSV52532000; COSMIC: COSV52532000;