6-112148260-C-T
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_001105206.3(LAMA4):c.2250G>A(p.Gln750=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 1 hom. )
Consequence
LAMA4
NM_001105206.3 synonymous
NM_001105206.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.659
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.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
Variant 6-112148260-C-T is Benign according to our data. Variant chr6-112148260-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112148260-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.659 with no splicing effect.
BS2
High AC in GnomAd4 at 257 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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LAMA4 | NM_001105206.3 | c.2250G>A | p.Gln750= | synonymous_variant | 18/39 | ENST00000230538.12 | NP_001098676.2 | |
LOC107986633 | XR_001744299.2 | n.440-7060C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.2250G>A | p.Gln750= | synonymous_variant | 18/39 | 1 | NM_001105206.3 | ENSP00000230538 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00170 AC: 258AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000458 AC: 115AN: 251222Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135758
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GnomAD4 exome AF: 0.000133 AC: 195AN: 1461848Hom.: 1 Cov.: 31 AF XY: 0.000111 AC XY: 81AN XY: 727232
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GnomAD4 genome AF: 0.00169 AC: 257AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.00162 AC XY: 121AN XY: 74492
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2015 | 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. - |
Dilated cardiomyopathy 1JJ Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2016 | This alteration is classified as likely 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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