1-209625908-A-T

Variant names:

• chr1-209625908-A-T
• rs2179402
• NM_000228.3:c.1716T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000228.3(LAMB3):​c.1716T>A​(p.Cys572*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C572C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 35)
• Consequence: LAMB3 NM_000228.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966
• Publications: 21 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1716T>A	p.Cys572*	stop_gained	Exon 14 of 23	NP_000219.2
	LAMB3	NM_001017402.2		c.1716T>A	p.Cys572*	stop_gained	Exon 13 of 22	NP_001017402.1
	LAMB3	NM_001127641.1		c.1716T>A	p.Cys572*	stop_gained	Exon 14 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.1716T>A	p.Cys572*	stop_gained	Exon 14 of 23	ENSP00000348384.3
	LAMB3	ENST00000367030.7	TSL:1	c.1716T>A	p.Cys572*	stop_gained	Exon 14 of 23	ENSP00000355997.3
	LAMB3	ENST00000391911.5	TSL:1	c.1716T>A	p.Cys572*	stop_gained	Exon 13 of 22	ENSP00000375778.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.28	N
PhyloP100		-0.97
Vest4		0.84
GERP RS		-5.7
Mutation Taster		=2/198	disease causing (fs/PTC)

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: rs2179402; hg19: chr1-209799253;