rs552326056

Positions:

chr18-23867900-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PVS1PM2BP6BS1

The NM_198129.4(LAMA3):c.4750C>T(p.Arg1584Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

LAMA3
NM_198129.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.01

Variant links:

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

LAMA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 18-23867900-C-T is Benign according to our data. Variant chr18-23867900-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551372.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000722 (11/152266) while in subpopulation EAS AF= 0.00154 (8/5184). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4 linkuse as main transcript	c.4750C>T	p.Arg1584Ter	stop_gained	37/75	ENST00000313654.14	NP_937762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14 linkuse as main transcript	c.4750C>T	p.Arg1584Ter	stop_gained	37/75	1	NM_198129.4	ENSP00000324532	P1	Q16787-2
LAMA3	ENST00000399516.7 linkuse as main transcript	c.4750C>T	p.Arg1584Ter	stop_gained	37/74	1		ENSP00000382432		Q16787-3
LAMA3	ENST00000649721.1 linkuse as main transcript	c.1642C>T	p.Arg548Ter	stop_gained	12/48			ENSP00000497885

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249548

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00139

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461690

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00219

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000121

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 06, 2017

- -

Junctional epidermolysis bullosa gravis of Herlitz;C1328355:Laryngo-onycho-cutaneous syndrome;C5676936:Epidermolysis bullosa, junctional 2A, intermediate;C5676937:Epidermolysis bullosa, junctional 2B, severe

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.20

Eigen_PC

Benign

-0.079

FATHMM_MKL

Benign

0.44

MutationTaster

Benign

1.0

A;A

Vest4

0.89

GERP RS

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over