rs3179860

Variant names:

• chr1-209622564-T-C
• rs3179860
• NM_000228.3:c.2673A>G

Variant summary

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

The NM_000228.3(LAMB3):​c.2673A>G​(p.Leu891Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,810 control chromosomes in the GnomAD database, including 17,970 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. L891L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1192 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16778 hom.)
• Consequence: LAMB3 NM_000228.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.74
• Publications: 12 publications found

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

LAMB3 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• junctional epidermolysis bullosa Herlitz type

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, PanelApp Australia
• amelogenesis imperfecta type 1A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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=-0.59).
• BP6: Variant 1-209622564-T-C is Benign according to our data. Variant chr1-209622564-T-C is described in ClinVar as Benign. ClinVar VariationId is 255589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000228.3. 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
	LAMB3	NM_000228.3	MANE Select	c.2673A>G	p.Leu891Leu	synonymous	Exon 18 of 23	NP_000219.2	A0A0S2Z3R6
	LAMB3	NM_001017402.2		c.2673A>G	p.Leu891Leu	synonymous	Exon 17 of 22	NP_001017402.1	Q13751
	LAMB3	NM_001127641.1		c.2673A>G	p.Leu891Leu	synonymous	Exon 18 of 23	NP_001121113.1	A0A0S2Z3R6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB3	ENST00000356082.9	TSL:1 MANE Select	c.2673A>G	p.Leu891Leu	synonymous	Exon 18 of 23	ENSP00000348384.3	Q13751
	LAMB3	ENST00000367030.7	TSL:1	c.2673A>G	p.Leu891Leu	synonymous	Exon 18 of 23	ENSP00000355997.3	Q13751
	LAMB3	ENST00000391911.5	TSL:1	c.2673A>G	p.Leu891Leu	synonymous	Exon 17 of 22	ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17443 AN: 151980 Hom.: 1193 Cov.: 32

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.128 AC: 32185 AN: 251456 AF XY: 0.137

Gnomad AFR exome AF: 0.0526

Gnomad AMR exome AF: 0.0744

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.146 AC: 213934 AN: 1461712 Hom.: 16778 Cov.: 34 AF XY: 0.149 AC XY: 108117 AN XY: 727168

African (AFR) AF: 0.0515 AC: 1725 AN: 33476

American (AMR) AF: 0.0780 AC: 3487 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3672 AN: 26136

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.199 AC: 17177 AN: 86250

European-Finnish (FIN) AF: 0.116 AC: 6219 AN: 53390

Middle Eastern (MID) AF: 0.132 AC: 755 AN: 5714

European-Non Finnish (NFE) AF: 0.155 AC: 172686 AN: 1111930

Other (OTH) AF: 0.136 AC: 8196 AN: 60392

GnomAD4 genome AF: 0.115 AC: 17443 AN: 152098 Hom.: 1192 Cov.: 32 AF XY: 0.113 AC XY: 8434 AN XY: 74334

African (AFR) AF: 0.0558 AC: 2315 AN: 41518

American (AMR) AF: 0.109 AC: 1658 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.200 AC: 960 AN: 4812

European-Finnish (FIN) AF: 0.114 AC: 1203 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10445 AN: 67952

Other (OTH) AF: 0.118 AC: 250 AN: 2114

Alfa AF: 0.142 Hom.: 2710

Bravo AF: 0.109

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Amelogenesis imperfecta type 1A (1)
-	-	1	Junctional epidermolysis bullosa (1)
-	-	1	Junctional epidermolysis bullosa gravis of Herlitz (1)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		1.7
Mutation Taster		=96/4	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: rs3179860; hg19: chr1-209795909; COSMIC: COSV61915903; COSMIC: COSV61915903;