chr18-23714056-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_198129.4(LAMA3):c.431C>G(p.Thr144Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,613,720 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00038 ( 1 hom. )
Consequence
LAMA3
NM_198129.4 missense
NM_198129.4 missense
Scores
6
6
3
Clinical Significance
Conservation
PhyloP100: 7.84
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.843
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000376 (549/1461828) while in subpopulation NFE AF= 0.00045 (500/1111960). AF 95% confidence interval is 0.000416. There are 1 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA3 | NM_198129.4 | c.431C>G | p.Thr144Ser | missense_variant | 2/75 | ENST00000313654.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA3 | ENST00000313654.14 | c.431C>G | p.Thr144Ser | missense_variant | 2/75 | 1 | NM_198129.4 | P1 | |
LAMA3 | ENST00000399516.7 | c.431C>G | p.Thr144Ser | missense_variant | 2/74 | 1 | |||
LAMA3 | ENST00000585600.5 | c.431C>G | p.Thr144Ser | missense_variant | 2/13 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 151892Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000156 AC: 39AN: 249512Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135370
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GnomAD4 exome AF: 0.000376 AC: 549AN: 1461828Hom.: 1 Cov.: 34 AF XY: 0.000352 AC XY: 256AN XY: 727222
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 151892Hom.: 0 Cov.: 30 AF XY: 0.000202 AC XY: 15AN XY: 74150
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2021 | The c.431C>G (p.T144S) alteration is located in exon 2 (coding exon 2) of the LAMA3 gene. This alteration results from a C to G substitution at nucleotide position 431, causing the threonine (T) at amino acid position 144 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Vest4
MutPred
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at