chr18-23907639-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_198129.4(LAMA3):​c.6808C>G​(p.Arg2270Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2270Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LAMA3
NM_198129.4 missense

Scores

7
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.08

Publications

4 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35237977).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMA3NM_198129.4 linkc.6808C>G p.Arg2270Gly missense_variant Exon 53 of 75 ENST00000313654.14 NP_937762.2 Q16787-2
LAMA3NM_000227.6 linkc.1981C>G p.Arg661Gly missense_variant Exon 16 of 38 ENST00000269217.11 NP_000218.3 Q16787-1A0A0A6YYF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMA3ENST00000313654.14 linkc.6808C>G p.Arg2270Gly missense_variant Exon 53 of 75 1 NM_198129.4 ENSP00000324532.8 Q16787-2
LAMA3ENST00000269217.11 linkc.1981C>G p.Arg661Gly missense_variant Exon 16 of 38 1 NM_000227.6 ENSP00000269217.5 Q16787-1A0A0A6YYF2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251486
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460950
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726844
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33448
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111170
Other (OTH)
AF:
0.00
AC:
0
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.032
.;T;.;.
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.79
.;T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.35
T;T;T;T
MetaSVM
Benign
-1.0
T
PhyloP100
4.1
PrimateAI
Benign
0.25
T
PROVEAN
Uncertain
-3.3
D;D;D;.
REVEL
Benign
0.14
Sift
Uncertain
0.0090
D;D;T;.
Sift4G
Uncertain
0.028
.;.;D;D
Vest4
0.38
MutPred
0.51
Loss of stability (P = 0.0952);.;.;.;
MVP
0.52
MPC
0.40
ClinPred
0.94
D
GERP RS
5.3
gMVP
0.37
Mutation Taster
=78/22
polymorphism

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

Other links and lift over

dbSNP: rs137852757; hg19: chr18-21487603; API