rs12748250

chr1-209622984-T-Achr1-209622984-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000228.3(LAMB3):c.2554A>T(p.Met852Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,870 control chromosomes in the GnomAD database, including 17,942 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1194 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16748 hom.)
• Consequence: LAMB3 NM_000228.3 missense, splice_region
• Scores: Splicing: ADA: 0.06802
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013975799).
• BP6: Variant 1-209622984-T-A is Benign according to our data. Variant chr1-209622984-T-A is described in ClinVar as [Benign]. Clinvar id is 255588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	1		P1
LAMB3	ENST00000391911.5	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	16/22	1		P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17436 AN: 152072 Hom.: 1195 Cov.: 32

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.128 AC: 31787 AN: 248634 Hom.: 2499 AF XY: 0.137 AC XY: 18427 AN XY: 134996

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.0743

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.000438

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.146 AC: 213631 AN: 1460680 Hom.: 16748 Cov.: 34 AF XY: 0.149 AC XY: 107970 AN XY: 726668

Gnomad4 AFR exome AF: 0.0513

Gnomad4 AMR exome AF: 0.0779

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.115 AC: 17436 AN: 152190 Hom.: 1194 Cov.: 32 AF XY: 0.113 AC XY: 8435 AN XY: 74412

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.119

Alfa AF: 0.142 Hom.: 1255

Bravo AF: 0.109

TwinsUK AF: 0.162 AC: 599

ALSPAC AF: 0.160 AC: 618

ESP6500AA AF: 0.0536 AC: 236

ESP6500EA AF: 0.153 AC: 1313

ExAC AF: 0.132 AC: 16021

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2018	Variant summary: LAMB3 c.2554A>T (p.Met852Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.13 in 275034 control chromosomes in the gnomAD database, including 2706 homozygotes (gnomAD). The observed variant frequency is approximately 135-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa phenotype (0.00093), strongly suggesting that the variant is benign. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Amelogenesis imperfecta type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Benign	0.91
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	0.48	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.029	B;B;B
Vest4		0.10
MutPred		0.18		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MPC		0.12
ClinPred		0.010	T
GERP RS		5.2
Varity_R		0.22
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.068
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12748250; hg19: chr1-209796329; COSMIC: COSV61916093; COSMIC: COSV61916093;