NM_000228.3:c.1579G>A

Variant names:

• chr1-209626885-C-T
• rs2076349
• NM_000228.3:c.1579G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000228.3(LAMB3):​c.1579G>A​(p.Val527Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,613,446 control chromosomes in the GnomAD database, including 14,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2724 hom., cov: 33)
  • Exomes 𝑓: 0.063 (11659 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.601
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3354112E-5).
• BP6: Variant 1-209626885-C-T is Benign according to our data. Variant chr1-209626885-C-T is described in ClinVar as Benign. ClinVar VariationId is 255586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 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.1579G>A	p.Val527Met	missense	Exon 13 of 23	NP_000219.2	A0A0S2Z3R6
	LAMB3	NM_001017402.2		c.1579G>A	p.Val527Met	missense	Exon 12 of 22	NP_001017402.1	Q13751
	LAMB3	NM_001127641.1		c.1579G>A	p.Val527Met	missense	Exon 13 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.1579G>A	p.Val527Met	missense	Exon 13 of 23	ENSP00000348384.3	Q13751
	LAMB3	ENST00000367030.7	TSL:1	c.1579G>A	p.Val527Met	missense	Exon 13 of 23	ENSP00000355997.3	Q13751
	LAMB3	ENST00000391911.5	TSL:1	c.1579G>A	p.Val527Met	missense	Exon 12 of 22	ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19792 AN: 152182 Hom.: 2710 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.132 AC: 32973 AN: 250462 AF XY: 0.118

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.581

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0888

GnomAD4 exome AF: 0.0632 AC: 92355 AN: 1461146 Hom.: 11659 Cov.: 32 AF XY: 0.0627 AC XY: 45604 AN XY: 726892

African (AFR) AF: 0.285 AC: 9527 AN: 33452

American (AMR) AF: 0.289 AC: 12920 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26130

East Asian (EAS) AF: 0.577 AC: 22894 AN: 39672

South Asian (SAS) AF: 0.110 AC: 9463 AN: 86216

European-Finnish (FIN) AF: 0.0208 AC: 1105 AN: 53164

Middle Eastern (MID) AF: 0.0739 AC: 426 AN: 5766

European-Non Finnish (NFE) AF: 0.0271 AC: 30178 AN: 1111684

Other (OTH) AF: 0.0888 AC: 5363 AN: 60362

GnomAD4 genome AF: 0.130 AC: 19855 AN: 152300 Hom.: 2724 Cov.: 33 AF XY: 0.132 AC XY: 9830 AN XY: 74466

African (AFR) AF: 0.267 AC: 11099 AN: 41560

American (AMR) AF: 0.185 AC: 2832 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.572 AC: 2956 AN: 5166

South Asian (SAS) AF: 0.118 AC: 570 AN: 4824

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10630

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1885 AN: 68026

Other (OTH) AF: 0.120 AC: 254 AN: 2114

Alfa AF: 0.0786 Hom.: 4326

Bravo AF: 0.155

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.254 AC: 1119

ESP6500EA AF: 0.0271 AC: 233

ExAC AF: 0.125 AC: 15136

Asia WGS AF: 0.308 AC: 1073 AN: 3478

EpiCase AF: 0.0297

EpiControl AF: 0.0263

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.60
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.035
Sift	Benign	0.068	T
Sift4G	Benign	0.074	T
Polyphen		0.60	P
Vest4		0.023
MPC		0.13
ClinPred		0.0076	T
GERP RS		-2.5
Varity_R		0.074
gMVP		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2076349; hg19: chr1-209800230; COSMIC: COSV61914969; COSMIC: COSV61914969;