rs35605307

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_001105206.3(LAMA4):ā€‹c.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

Scores

8
6
3

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.52
Variant links:
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]

Genome browser will be placed here

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
LAMA4NM_001105206.3 linkuse as main transcriptc.2810A>G p.Glu937Gly missense_variant 21/39 ENST00000230538.12
LOC107986633XR_001744299.2 linkuse as main transcriptn.440-13959T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LAMA4ENST00000230538.12 linkuse as main transcriptc.2810A>G p.Glu937Gly missense_variant 21/391 NM_001105206.3 A1

Frequencies

GnomAD3 genomes
AF:
0.00331
AC:
503
AN:
152152
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0116
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000868
AC:
218
AN:
251190
Hom.:
2
AF XY:
0.000633
AC XY:
86
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.0124
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.000364
AC:
532
AN:
1461800
Hom.:
4
Cov.:
32
AF XY:
0.000297
AC XY:
216
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.0130
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000894
GnomAD4 genome
AF:
0.00336
AC:
512
AN:
152270
Hom.:
6
Cov.:
32
AF XY:
0.00337
AC XY:
251
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.0118
Gnomad4 AMR
AF:
0.00111
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000550
Hom.:
1
Bravo
AF:
0.00354
ESP6500AA
AF:
0.00772
AC:
34
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00119
AC:
145
Asia WGS
AF:
0.00346
AC:
12
AN:
3478

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 providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 18, 2012Glu930Gly 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 submitterclinical testingGeneDxJul 08, 2014This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 03, 2023- -
Dilated cardiomyopathy 1JJ Benign:3
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 04, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 17, 2024- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterMay 31, 2017- -
Primary dilated cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoAug 21, 2017- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 28, 2015This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.027
T
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.14
T;T;T;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;.;.;D
MetaRNN
Benign
0.013
T;T;T;T
MetaSVM
Uncertain
0.085
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.5
D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.019
D;D;D;D
Sift4G
Uncertain
0.020
D;D;D;D
Vest4
0.94
MVP
0.87
MPC
0.49
ClinPred
0.023
T
GERP RS
5.7
gMVP
0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35605307; hg19: chr6-112462563; API