rs35605307
Positions:
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2
The NM_001105206.3(LAMA4):āc.2810A>Gā(p.Glu937Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0034 ( 6 hom., cov: 32)
Exomes š: 0.00036 ( 4 hom. )
Consequence
LAMA4
NM_001105206.3 missense
NM_001105206.3 missense
Scores
8
6
3
Clinical Significance
Conservation
PhyloP100: 7.52
Genes affected
LAMA4 (HGNC:6484): (laminin subunit alpha 4) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the alpha chain isoform laminin, alpha 4. The domain structure of alpha 4 is similar to that of alpha 3, both of which resemble truncated versions of alpha 1 and alpha 2, in that approximately 1,200 residues at the N-terminus (domains IV, V and VI) have been lost. Laminin, alpha 4 contains the C-terminal G domain which distinguishes all alpha chains from the beta and gamma chains. The RNA analysis from adult and fetal tissues revealed developmental regulation of expression, however, the exact function of laminin, alpha 4 is not known. Tissue-specific utilization of alternative polyA-signal has been described in literature. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.012752295).
BP6
Variant 6-112141361-T-C is Benign according to our data. Variant chr6-112141361-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112141361-T-C is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 512 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA4 | NM_001105206.3 | c.2810A>G | p.Glu937Gly | missense_variant | 21/39 | ENST00000230538.12 | |
LOC107986633 | XR_001744299.2 | n.440-13959T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.2810A>G | p.Glu937Gly | missense_variant | 21/39 | 1 | NM_001105206.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00331 AC: 503AN: 152152Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.000868 AC: 218AN: 251190Hom.: 2 AF XY: 0.000633 AC XY: 86AN XY: 135756
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GnomAD4 exome AF: 0.000364 AC: 532AN: 1461800Hom.: 4 Cov.: 32 AF XY: 0.000297 AC XY: 216AN XY: 727210
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GnomAD4 genome AF: 0.00336 AC: 512AN: 152270Hom.: 6 Cov.: 32 AF XY: 0.00337 AC XY: 251AN XY: 74454
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 18, 2012 | Glu930Gly in exon 21 of LAMA4: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (30/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35605307). Glu930Gly in exon 21 of LAMA4 (r s35605307; allele frequency = 0.8%, 30/3738) ** - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2023 | - - |
Dilated cardiomyopathy 1JJ Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 04, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
Primary dilated cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Aug 21, 2017 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 28, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Vest4
MVP
MPC
ClinPred
T
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