rs55824996

Variant names:

• chr1-209637948-T-C
• rs55824996
• NM_000228.3:c.332A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-209637948-T-C
• chr1-209637948-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000228.3(LAMB3):​c.332A>G​(p.Asp111Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000387 in 1,613,360 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D111D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.82
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007794291).
• BP6: Variant 1-209637948-T-C is Benign according to our data. Variant chr1-209637948-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255594.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00217 (330/152214) while in subpopulation AFR AF = 0.00754 (313/41518). AF 95% confidence interval is 0.00685. There are 3 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.332A>G	p.Asp111Gly	missense	Exon 5 of 23	NP_000219.2	A0A0S2Z3R6
	LAMB3	NM_001017402.2		c.332A>G	p.Asp111Gly	missense	Exon 4 of 22	NP_001017402.1	Q13751
	LAMB3	NM_001127641.1		c.332A>G	p.Asp111Gly	missense	Exon 5 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.332A>G	p.Asp111Gly	missense	Exon 5 of 23	ENSP00000348384.3	Q13751
	LAMB3	ENST00000367030.7	TSL:1	c.332A>G	p.Asp111Gly	missense	Exon 5 of 23	ENSP00000355997.3	Q13751
	LAMB3	ENST00000391911.5	TSL:1	c.332A>G	p.Asp111Gly	missense	Exon 4 of 22	ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152096 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000504 AC: 126 AN: 249806 AF XY: 0.000385

Gnomad AFR exome AF: 0.00753

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461146 Hom.: 2 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 726828

African (AFR) AF: 0.00771 AC: 258 AN: 33468

American (AMR) AF: 0.000269 AC: 12 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111718

Other (OTH) AF: 0.000364 AC: 22 AN: 60372

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152214 Hom.: 3 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74424

African (AFR) AF: 0.00754 AC: 313 AN: 41518

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000783 Hom.: 1

Bravo AF: 0.00261

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000741 AC: 90

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.41
MVP		0.88
MPC		0.20
ClinPred		0.063	T
GERP RS		4.1
Varity_R		0.40
gMVP		0.53
Mutation Taster		=95/5	polymorphism

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: rs55824996; hg19: chr1-209811293;