Genetic Variant NM_000228.3:c.291A>C (chr1-209638541-T-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.291A>C(p.Ser97Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,601,282 control chromosomes in the GnomAD database, including 308,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S97S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.56 ( 25024 hom., cov: 32)

Exomes 𝑓: 0.62 ( 283721 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.889

Publications

25 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=-0.81).

BP6

Variant 1-209638541-T-G is Benign according to our data. Variant chr1-209638541-T-G is described in ClinVar as Benign. ClinVar VariationId is 255592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.889 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.645 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.291A>C	p.Ser97Ser	synonymous	Exon 4 of 23	NP_000219.2
LAMB3	NM_001017402.2		c.291A>C	p.Ser97Ser	synonymous	Exon 3 of 22	NP_001017402.1
LAMB3	NM_001127641.1		c.291A>C	p.Ser97Ser	synonymous	Exon 4 of 23	NP_001121113.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMB3	ENST00000356082.9	TSL:1 MANE Select	c.291A>C	p.Ser97Ser	synonymous	Exon 4 of 23	ENSP00000348384.3
LAMB3	ENST00000367030.7	TSL:1	c.291A>C	p.Ser97Ser	synonymous	Exon 4 of 23	ENSP00000355997.3
LAMB3	ENST00000391911.5	TSL:1	c.291A>C	p.Ser97Ser	synonymous	Exon 3 of 22	ENSP00000375778.1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85028

AN:

151932

Hom.:

25022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.752

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.675

Gnomad EAS

AF:

0.276

Gnomad SAS

AF:

0.482

Gnomad FIN

AF:

0.718

Gnomad MID

AF:

0.723

Gnomad NFE

AF:

0.650

Gnomad OTH

AF:

0.574

GnomAD2 exomes

AF:

0.568

AC:

142705

AN:

251300

AF XY:

0.574

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.444

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.702

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.619

AC:

896976

AN:

1449232

Hom.:

283721

Cov.:

AF XY:

0.617

AC XY:

445418

AN XY:

721706

show subpopulations

African (AFR)

AF:

0.411

AC:

13652

AN:

33246

American (AMR)

AF:

0.448

AC:

20014

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

17740

AN:

26056

East Asian (EAS)

AF:

0.291

AC:

11534

AN:

39658

South Asian (SAS)

AF:

0.498

AC:

42859

AN:

85998

European-Finnish (FIN)

AF:

0.706

AC:

37731

AN:

53406

Middle Eastern (MID)

AF:

0.674

AC:

3870

AN:

5738

European-Non Finnish (NFE)

AF:

0.649

AC:

713892

AN:

1100440

Other (OTH)

AF:

0.595

AC:

35684

AN:

59986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15853

31706

47558

63411

79264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18404

36808

55212

73616

92020

<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:

0.559

AC:

85069

AN:

152050

Hom.:

25024

Cov.:

AF XY:

0.559

AC XY:

41557

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.420

AC:

17407

AN:

41470

American (AMR)

AF:

0.502

AC:

7675

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

2341

AN:

3468

East Asian (EAS)

AF:

0.276

AC:

1428

AN:

5170

South Asian (SAS)

AF:

0.483

AC:

2327

AN:

4814

European-Finnish (FIN)

AF:

0.718

AC:

7583

AN:

10562

Middle Eastern (MID)

AF:

0.705

AC:

206

AN:

292

European-Non Finnish (NFE)

AF:

0.650

AC:

44209

AN:

67966

Other (OTH)

AF:

0.572

AC:

1209

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1843

3686

5529

7372

9215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.615

Hom.:

43973

Bravo

AF:

0.536

Asia WGS

AF:

0.390

AC:

1355

AN:

3478

EpiCase

AF:

0.644

EpiControl

AF:

0.650

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 02, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.3

(source)

DANN

Benign

0.50

PhyloP100

-0.89

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