1-209615358-T-C

Variant names:

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.3432A>G(p.Ser1144Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,612,508 control chromosomes in the GnomAD database, including 118,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15536 hom., cov: 33)

Exomes 𝑓: 0.37 ( 103158 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.67

Publications

16 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=-0.86).

BP6

Variant 1-209615358-T-C is Benign according to our data. Variant chr1-209615358-T-C is described in ClinVar as Benign. ClinVar VariationId is 255595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.67 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.3432A>G	p.Ser1144Ser	synonymous_variant	Exon 23 of 23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LAMB3	ENST00000356082.9 link	c.3432A>G	p.Ser1144Ser	synonymous_variant	Exon 23 of 23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7 link	c.3432A>G	p.Ser1144Ser	synonymous_variant	Exon 23 of 23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5 link	c.3432A>G	p.Ser1144Ser	synonymous_variant	Exon 22 of 22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66644

AN:

151998

Hom.:

15520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.389

Gnomad ASJ

AF:

0.407

Gnomad EAS

AF:

0.409

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.394

AC:

98338

AN:

249352

AF XY:

0.390

show subpopulations

Gnomad AFR exome

AF:

0.619

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.430

Gnomad EAS exome

AF:

0.416

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.361

Gnomad OTH exome

AF:

0.375

GnomAD4 exome

AF:

0.373

AC:

544006

AN:

1460392

Hom.:

103158

Cov.:

AF XY:

0.373

AC XY:

270932

AN XY:

726446

show subpopulations

African (AFR)

AF:

0.618

AC:

20656

AN:

33430

American (AMR)

AF:

0.376

AC:

16811

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

10988

AN:

26094

East Asian (EAS)

AF:

0.415

AC:

16439

AN:

39634

South Asian (SAS)

AF:

0.401

AC:

34580

AN:

86134

European-Finnish (FIN)

AF:

0.386

AC:

20527

AN:

53130

Middle Eastern (MID)

AF:

0.338

AC:

1945

AN:

5758

European-Non Finnish (NFE)

AF:

0.359

AC:

399004

AN:

1111198

Other (OTH)

AF:

0.382

AC:

23056

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

18296

36591

54887

73182

91478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12824

25648

38472

51296

64120

<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:

0.439

AC:

66704

AN:

152116

Hom.:

15536

Cov.:

AF XY:

0.437

AC XY:

32518

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.611

AC:

25334

AN:

41484

American (AMR)

AF:

0.389

AC:

5945

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

1413

AN:

3470

East Asian (EAS)

AF:

0.408

AC:

2110

AN:

5166

South Asian (SAS)

AF:

0.407

AC:

1962

AN:

4822

European-Finnish (FIN)

AF:

0.404

AC:

4279

AN:

10586

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.360

AC:

24437

AN:

67972

Other (OTH)

AF:

0.419

AC:

887

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1864

3728

5592

7456

9320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.391

Hom.:

11628

Bravo

AF:

0.443

Asia WGS

AF:

0.406

AC:

1416

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 12, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.035

(source)

DANN

Benign

0.59

PhyloP100

-4.7

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over