dbSNP rs2179402: LAMB3:p.Cys572Cys (chr1-209625908-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000228.3(LAMB3):c.1716T>C(p.Cys572Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 1,613,420 control chromosomes in the GnomAD database, including 441,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42713 hom., cov: 35)

Exomes 𝑓: 0.74 ( 398928 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.966

Publications

21 publications found

Variant links:

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

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-209625908-A-G is Benign according to our data. Variant chr1-209625908-A-G is described in ClinVar as Benign. ClinVar VariationId is 255587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.966 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMB3	NM_000228.3	MANE Select	c.1716T>C	p.Cys572Cys	synonymous	Exon 14 of 23	NP_000219.2
LAMB3	NM_001017402.2		c.1716T>C	p.Cys572Cys	synonymous	Exon 13 of 22	NP_001017402.1
LAMB3	NM_001127641.1		c.1716T>C	p.Cys572Cys	synonymous	Exon 14 of 23	NP_001121113.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMB3	ENST00000356082.9	TSL:1 MANE Select	c.1716T>C	p.Cys572Cys	synonymous	Exon 14 of 23	ENSP00000348384.3
LAMB3	ENST00000367030.7	TSL:1	c.1716T>C	p.Cys572Cys	synonymous	Exon 14 of 23	ENSP00000355997.3
LAMB3	ENST00000391911.5	TSL:1	c.1716T>C	p.Cys572Cys	synonymous	Exon 13 of 22	ENSP00000375778.1

Frequencies

GnomAD3 genomes

AF:

0.749

AC:

113899

AN:

152116

Hom.:

42675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.771

Gnomad AMI

AF:

0.794

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.814

Gnomad EAS

AF:

0.823

Gnomad SAS

AF:

0.740

Gnomad FIN

AF:

0.740

Gnomad MID

AF:

0.763

Gnomad NFE

AF:

0.727

Gnomad OTH

AF:

0.745

GnomAD2 exomes

AF:

0.754

AC:

187810

AN:

249024

AF XY:

0.753

show subpopulations

Gnomad AFR exome

AF:

0.769

Gnomad AMR exome

AF:

0.773

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.823

Gnomad FIN exome

AF:

0.732

Gnomad NFE exome

AF:

0.737

Gnomad OTH exome

AF:

0.739

GnomAD4 exome

AF:

0.738

AC:

1078370

AN:

1461186

Hom.:

398928

Cov.:

AF XY:

0.739

AC XY:

536973

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.768

AC:

25704

AN:

33476

American (AMR)

AF:

0.769

AC:

34314

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

21501

AN:

26104

East Asian (EAS)

AF:

0.838

AC:

33268

AN:

39686

South Asian (SAS)

AF:

0.742

AC:

63959

AN:

86254

European-Finnish (FIN)

AF:

0.730

AC:

38874

AN:

53234

Middle Eastern (MID)

AF:

0.801

AC:

4621

AN:

5768

European-Non Finnish (NFE)

AF:

0.730

AC:

810971

AN:

1111676

Other (OTH)

AF:

0.748

AC:

45158

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18832

37665

56497

75330

94162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20068

40136

60204

80272

100340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.749

AC:

113992

AN:

152234

Hom.:

42713

Cov.:

AF XY:

0.751

AC XY:

55894

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.771

AC:

32047

AN:

41556

American (AMR)

AF:

0.752

AC:

11502

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.814

AC:

2824

AN:

3470

East Asian (EAS)

AF:

0.823

AC:

4259

AN:

5172

South Asian (SAS)

AF:

0.740

AC:

3568

AN:

4824

European-Finnish (FIN)

AF:

0.740

AC:

7838

AN:

10596

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.727

AC:

49432

AN:

67992

Other (OTH)

AF:

0.746

AC:

1577

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1526

3052

4579

6105

7631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.742

Hom.:

76518

Bravo

AF:

0.751

Asia WGS

AF:

0.736

AC:

2560

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Amelogenesis imperfecta type 1A

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Junctional epidermolysis bullosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.27

(source)

DANN

Benign

0.56

PhyloP100

-0.97

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over