dbSNP rs772038362: LAMA3:p.Gln2981Lys (chr18-23939301-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198129.4(LAMA3):c.8941C>A(p.Gln2981Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LAMA3
NM_198129.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.130

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
laryngo-onycho-cutaneous syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056633443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4 link	c.8941C>A	p.Gln2981Lys	missense_variant	Exon 68 of 75	ENST00000313654.14	NP_937762.2	Q16787-2
LAMA3	NM_000227.6 link	c.4114C>A	p.Gln1372Lys	missense_variant	Exon 31 of 38	ENST00000269217.11	NP_000218.3	Q16787-1A0A0A6YYF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14 link	c.8941C>A	p.Gln2981Lys	missense_variant	Exon 68 of 75	1	NM_198129.4	ENSP00000324532.8		Q16787-2
LAMA3	ENST00000269217.11 link	c.4114C>A	p.Gln1372Lys	missense_variant	Exon 31 of 38	1	NM_000227.6	ENSP00000269217.5		Q16787-1A0A0A6YYF2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.3

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.013

.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.64

.;T;T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

0.13

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.46

N;N;.;N;.

REVEL

Benign

0.026

Sift

Benign

0.56

T;T;.;T;.

Sift4G

Benign

0.96

.;.;.;T;T

Vest4

0.16

MutPred

0.41

Gain of ubiquitination at Q2981 (P = 0.0104);.;.;.;.;

MVP

0.072

MPC

0.15

ClinPred

0.019

GERP RS

3.4

gMVP

0.33

Mutation Taster

=94/6

polymorphism

(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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rs772038362

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over