1-209615311-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000228.3(LAMB3):c.3479A>G(p.His1160Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008704871).
• BP6: Variant 1-209615311-T-C is Benign according to our data. Variant chr1-209615311-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295060.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3	c.3479A>G	p.His1160Arg	missense_variant	23/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.3479A>G	p.His1160Arg	missense_variant	23/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.3479A>G	p.His1160Arg	missense_variant	23/23	1		P1
LAMB3	ENST00000391911.5	c.3479A>G	p.His1160Arg	missense_variant	22/22	1		P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251242 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135794

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000537 AC: 785 AN: 1461786 Hom.: 1 Cov.: 30 AF XY: 0.000524 AC XY: 381 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00601

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74368

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000645 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000764

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Junctional epidermolysis bullosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.61	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.20	B;B;B
Vest4		0.17
MVP		0.46
MPC		0.18
ClinPred		0.030	T
GERP RS		5.6
Varity_R		0.055
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs147931502; hg19: chr1-209788656; COSMIC: COSV99049402; COSMIC: COSV99049402;