rs12748250

Variant names:

• chr1-209622984-T-A
• rs12748250
• NM_000228.3:c.2554A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-209622984-T-A
• chr1-209622984-T-C

Variant summary

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

The ENST00000356082.9(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. 15/23 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M852V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1194 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16748 hom.)
• Consequence: LAMB3 ENST00000356082.9 missense, splice_region
• Scores: Splicing: ADA: 0.06802
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.29
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine
• junctional epidermolysis bullosa, non-Herlitz type

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356082.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB3	NM_000228.3	MANE Select	c.2554A>T	p.Met852Leu	missense splice_region	Exon 17 of 23	NP_000219.2
	LAMB3	NM_001017402.2		c.2554A>T	p.Met852Leu	missense splice_region	Exon 16 of 22	NP_001017402.1
	LAMB3	NM_001127641.1		c.2554A>T	p.Met852Leu	missense splice_region	Exon 17 of 23	NP_001121113.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB3	ENST00000356082.9	TSL:1 MANE Select	c.2554A>T	p.Met852Leu	missense splice_region	Exon 17 of 23	ENSP00000348384.3
	LAMB3	ENST00000367030.7	TSL:1	c.2554A>T	p.Met852Leu	missense splice_region	Exon 17 of 23	ENSP00000355997.3
	LAMB3	ENST00000391911.5	TSL:1	c.2554A>T	p.Met852Leu	missense splice_region	Exon 16 of 22	ENSP00000375778.1

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

GnomAD2 exomes AF: 0.128 AC: 31787 AN: 248634 AF XY: 0.137

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 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

African (AFR) AF: 0.0513 AC: 1716 AN: 33454

American (AMR) AF: 0.0779 AC: 3485 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3671 AN: 26134

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

South Asian (SAS) AF: 0.199 AC: 17140 AN: 86198

European-Finnish (FIN) AF: 0.117 AC: 6218 AN: 53324

Middle Eastern (MID) AF: 0.132 AC: 656 AN: 4980

European-Non Finnish (NFE) AF: 0.155 AC: 172549 AN: 1111872

Other (OTH) AF: 0.136 AC: 8179 AN: 60296

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

African (AFR) AF: 0.0555 AC: 2307 AN: 41534

American (AMR) AF: 0.109 AC: 1660 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3464

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.198 AC: 955 AN: 4822

European-Finnish (FIN) AF: 0.114 AC: 1213 AN: 10608

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10438 AN: 67972

Other (OTH) AF: 0.119 AC: 251 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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
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
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.55	T
Sift4G	Benign	0.20	T
Polyphen		0.029	B
Vest4		0.10
MutPred		0.18		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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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