rs1130667

Variant names:

• chr1-209634627-G-A
• rs1130667
• NM_000228.3:c.384C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-209634627-G-A
• chr1-209634627-G-C
• chr1-209634627-G-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_000228.3(LAMB3):​c.384C>T​(p.Pro128Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,611,392 control chromosomes in the GnomAD database, including 118,728 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. P128P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (8286 hom., cov: 30)
  • Exomes 𝑓: 0.38 (110442 hom.)
• Consequence: LAMB3 NM_000228.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.01
• Publications: 16 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: Orphanet, Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• 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=-0.64).
• BP6: Variant 1-209634627-G-A is Benign according to our data. Variant chr1-209634627-G-A is described in ClinVar as Benign. ClinVar VariationId is 255596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.393 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.384C>T	p.Pro128Pro	synonymous	Exon 6 of 23	NP_000219.2	A0A0S2Z3R6
	LAMB3	NM_001017402.2		c.384C>T	p.Pro128Pro	synonymous	Exon 5 of 22	NP_001017402.1	Q13751
	LAMB3	NM_001127641.1		c.384C>T	p.Pro128Pro	synonymous	Exon 6 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.384C>T	p.Pro128Pro	synonymous	Exon 6 of 23	ENSP00000348384.3	Q13751
	LAMB3	ENST00000367030.7	TSL:1	c.384C>T	p.Pro128Pro	synonymous	Exon 6 of 23	ENSP00000355997.3	Q13751
	LAMB3	ENST00000391911.5	TSL:1	c.384C>T	p.Pro128Pro	synonymous	Exon 5 of 22	ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47036 AN: 151696 Hom.: 8286 Cov.: 30

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.342 AC: 84343 AN: 246344 AF XY: 0.352

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.383 AC: 559312 AN: 1459574 Hom.: 110442 Cov.: 39 AF XY: 0.383 AC XY: 278120 AN XY: 726098

African (AFR) AF: 0.132 AC: 4407 AN: 33456

American (AMR) AF: 0.217 AC: 9691 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10290 AN: 26106

East Asian (EAS) AF: 0.250 AC: 9893 AN: 39618

South Asian (SAS) AF: 0.337 AC: 28987 AN: 86104

European-Finnish (FIN) AF: 0.461 AC: 24535 AN: 53276

Middle Eastern (MID) AF: 0.463 AC: 2662 AN: 5744

European-Non Finnish (NFE) AF: 0.402 AC: 446509 AN: 1110364

Other (OTH) AF: 0.370 AC: 22338 AN: 60308

GnomAD4 genome AF: 0.310 AC: 47034 AN: 151818 Hom.: 8286 Cov.: 30 AF XY: 0.312 AC XY: 23136 AN XY: 74188

African (AFR) AF: 0.139 AC: 5771 AN: 41456

American (AMR) AF: 0.266 AC: 4059 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1379 AN: 3466

East Asian (EAS) AF: 0.241 AC: 1227 AN: 5090

South Asian (SAS) AF: 0.325 AC: 1565 AN: 4820

European-Finnish (FIN) AF: 0.458 AC: 4836 AN: 10550

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.397 AC: 26943 AN: 67850

Other (OTH) AF: 0.324 AC: 680 AN: 2102

Alfa AF: 0.337 Hom.: 6126

Bravo AF: 0.288

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.15
DANN	Benign	0.66
PhyloP100		-4.0
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: rs1130667; hg19: chr1-209807972; COSMIC: COSV61916410;