chr18-23857967-G-C

Variant names:

• chr18-23857967-G-C
• rs867449
• NM_198129.4:c.4260G>C

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.4260G>C​(p.Gly1420Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,613,780 control chromosomes in the GnomAD database, including 268,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1420G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (19255 hom., cov: 32)
  • Exomes 𝑓: 0.57 (249510 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.294
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 18-23857967-G-C is Benign according to our data. Variant chr18-23857967-G-C is described in ClinVar as Benign. ClinVar VariationId is 403026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.294 with no splicing effect.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.4260G>C	p.Gly1420Gly	synonymous	Exon 33 of 75	NP_937762.2	Q16787-2
	LAMA3	NM_001127717.4		c.4260G>C	p.Gly1420Gly	synonymous	Exon 33 of 74	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.4260G>C	p.Gly1420Gly	synonymous	Exon 33 of 75	ENSP00000324532.8	Q16787-2
	LAMA3	ENST00000399516.7	TSL:1	c.4260G>C	p.Gly1420Gly	synonymous	Exon 33 of 74	ENSP00000382432.2	Q16787-3
	LAMA3	ENST00000649721.1		c.1152G>C	p.Gly384Gly	synonymous	Exon 8 of 48	ENSP00000497885.1	A0A3B3ITG1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72109 AN: 151944 Hom.: 19256 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.513

GnomAD2 exomes AF: 0.494 AC: 123290 AN: 249472 AF XY: 0.504

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.572 AC: 836700 AN: 1461716 Hom.: 249510 Cov.: 56 AF XY: 0.570 AC XY: 414610 AN XY: 727180

African (AFR) AF: 0.245 AC: 8212 AN: 33474

American (AMR) AF: 0.366 AC: 16366 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 17379 AN: 26134

East Asian (EAS) AF: 0.138 AC: 5480 AN: 39698

South Asian (SAS) AF: 0.409 AC: 35300 AN: 86256

European-Finnish (FIN) AF: 0.562 AC: 30010 AN: 53412

Middle Eastern (MID) AF: 0.576 AC: 3323 AN: 5768

European-Non Finnish (NFE) AF: 0.618 AC: 687082 AN: 1111866

Other (OTH) AF: 0.556 AC: 33548 AN: 60388

GnomAD4 genome AF: 0.474 AC: 72119 AN: 152064 Hom.: 19255 Cov.: 32 AF XY: 0.466 AC XY: 34615 AN XY: 74338

African (AFR) AF: 0.258 AC: 10691 AN: 41468

American (AMR) AF: 0.451 AC: 6890 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2306 AN: 3472

East Asian (EAS) AF: 0.162 AC: 837 AN: 5172

South Asian (SAS) AF: 0.397 AC: 1914 AN: 4820

European-Finnish (FIN) AF: 0.548 AC: 5784 AN: 10562

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41846 AN: 67972

Other (OTH) AF: 0.509 AC: 1070 AN: 2104

Alfa AF: 0.591 Hom.: 8846

Bravo AF: 0.459

Asia WGS AF: 0.278 AC: 967 AN: 3478

EpiCase AF: 0.629

EpiControl AF: 0.628

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.78
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		0.29
Mutation Taster		=99/1	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: rs867449; hg19: chr18-21437931; COSMIC: COSV58065064;