rs2288592

Variant names:

• chr18-23946123-C-T
• rs2288592
• NM_198129.4:c.9211-21C>T

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.9211-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,607,248 control chromosomes in the GnomAD database, including 317,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22805 hom., cov: 30)
  • Exomes 𝑓: 0.62 (294692 hom.)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.09
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: 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=-0.9).
• BP6: Variant 18-23946123-C-T is Benign according to our data. Variant chr18-23946123-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 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.9211-21C>T		intron	N/A	NP_937762.2	Q16787-2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.4384-21C>T		intron	N/A	NP_000218.3
	LAMA3	NM_001127717.4		c.9043-21C>T		intron	N/A	NP_001121189.2	A0A0A0MSA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.9211-21C>T		intron	N/A	ENSP00000324532.8	Q16787-2
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.4384-21C>T		intron	N/A	ENSP00000269217.5	Q16787-1
	LAMA3	ENST00000399516.7	TSL:1	c.9043-21C>T		intron	N/A	ENSP00000382432.2	Q16787-3

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78049 AN: 151742 Hom.: 22806 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.534 AC: 134214 AN: 251384 AF XY: 0.546

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.622 AC: 905897 AN: 1455388 Hom.: 294692 Cov.: 33 AF XY: 0.620 AC XY: 449067 AN XY: 724342

African (AFR) AF: 0.251 AC: 8398 AN: 33392

American (AMR) AF: 0.388 AC: 17331 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 18229 AN: 26082

East Asian (EAS) AF: 0.138 AC: 5479 AN: 39676

South Asian (SAS) AF: 0.426 AC: 36664 AN: 86128

European-Finnish (FIN) AF: 0.633 AC: 33835 AN: 53410

Middle Eastern (MID) AF: 0.604 AC: 3471 AN: 5744

European-Non Finnish (NFE) AF: 0.675 AC: 746532 AN: 1106078

Other (OTH) AF: 0.598 AC: 35958 AN: 60164

GnomAD4 genome AF: 0.514 AC: 78061 AN: 151860 Hom.: 22805 Cov.: 30 AF XY: 0.506 AC XY: 37533 AN XY: 74238

African (AFR) AF: 0.268 AC: 11085 AN: 41382

American (AMR) AF: 0.484 AC: 7380 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2443 AN: 3468

East Asian (EAS) AF: 0.162 AC: 839 AN: 5170

South Asian (SAS) AF: 0.410 AC: 1968 AN: 4798

European-Finnish (FIN) AF: 0.627 AC: 6601 AN: 10528

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45777 AN: 67954

Other (OTH) AF: 0.546 AC: 1152 AN: 2110

Alfa AF: 0.616 Hom.: 82514

Bravo AF: 0.493

Asia WGS AF: 0.285 AC: 991 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.057
DANN	Benign	0.53
PhyloP100		-2.1
PromoterAI		-0.0085	Neutral
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: rs2288592; hg19: chr18-21526087; COSMIC: COSV52531938; COSMIC: COSV52531938;