rs2229467

Variant names:

• chr1-209617996-G-A
• rs2229467
• NM_000228.3:c.2962C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-209617996-G-A
• chr1-209617996-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000228.3(LAMB3):​c.2962C>T​(p.Arg988Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00093 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R988Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.46
• Publications: 10 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025251806).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB3	NM_000228.3	MANE Select	c.2962C>T	p.Arg988Trp	missense	Exon 20 of 23	NP_000219.2
	LAMB3	NM_001017402.2		c.2962C>T	p.Arg988Trp	missense	Exon 19 of 22	NP_001017402.1
	LAMB3	NM_001127641.1		c.2962C>T	p.Arg988Trp	missense	Exon 20 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.2962C>T	p.Arg988Trp	missense	Exon 20 of 23	ENSP00000348384.3
	LAMB3	ENST00000367030.7	TSL:1	c.2962C>T	p.Arg988Trp	missense	Exon 20 of 23	ENSP00000355997.3
	LAMB3	ENST00000391911.5	TSL:1	c.2962C>T	p.Arg988Trp	missense	Exon 19 of 22	ENSP00000375778.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000887 AC: 223 AN: 251470 AF XY: 0.000883

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000960 AC: 1403 AN: 1461868 Hom.: 1 Cov.: 33 AF XY: 0.000950 AC XY: 691 AN XY: 727238

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86258

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00103 AC: 1142 AN: 1111986

Other (OTH) AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74456

African (AFR) AF: 0.000144 AC: 6 AN: 41544

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00106 Hom.: 2

Bravo AF: 0.000676

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Junctional epidermolysis bullosa gravis of Herlitz (2)
-	2	-	not provided (2)
-	1	-	Junctional epidermolysis bullosa (1)
-	1	-	Junctional epidermolysis bullosa gravis of Herlitz;C0268374:Junctional epidermolysis bullosa, non-Herlitz type;C4011403:Amelogenesis imperfecta type 1A (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.061	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.80
MVP		0.58
MPC		0.39
ClinPred		0.038	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.32
Mutation Taster		=5/95	disease causing

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: rs2229467; hg19: chr1-209791341; COSMIC: COSV99151632;