rs538726706

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001105206.3(LAMA4):ā€‹c.1988T>Cā€‹(p.Ile663Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,613,268 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00021 ( 1 hom., cov: 32)
Exomes š‘“: 0.00034 ( 5 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.16
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 -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009232014).
BP6
Variant 6-112154919-A-G is Benign according to our data. Variant chr6-112154919-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 179474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LAMA4NM_001105206.3 linkuse as main transcriptc.1988T>C p.Ile663Thr missense_variant 16/39 ENST00000230538.12 NP_001098676.2 Q16363A0A0A0MQS9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LAMA4ENST00000230538.12 linkuse as main transcriptc.1988T>C p.Ile663Thr missense_variant 16/391 NM_001105206.3 ENSP00000230538.7 A0A0A0MQS9

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152180
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00600
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000661
AC:
166
AN:
251194
Hom.:
2
AF XY:
0.000913
AC XY:
124
AN XY:
135746
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 SAS exome
AF:
0.00526
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000338
AC:
494
AN:
1460970
Hom.:
5
Cov.:
29
AF XY:
0.000472
AC XY:
343
AN XY:
726896
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00530
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152298
Hom.:
1
Cov.:
32
AF XY:
0.000376
AC XY:
28
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00601
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000514
Hom.:
0
Bravo
AF:
0.0000604
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000717
AC:
87
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 06, 2024- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 26, 2013Ile656Thr in exon 16 of LAMA4: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 3 mammals (opossum, Tasmanian devil, and wallaby) and parrot have a threonin e (Thr) at this position despite high nearby amino acid conservation. In additio n, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high lik elihood of impact to the protein. -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 25, 2016This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 22, 2020This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
20
DANN
Benign
0.91
DEOGEN2
Benign
0.010
T;T;T;T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.082
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.78
T;.;.;T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.0092
T;T;T;T
MetaSVM
Benign
-0.96
T
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
0.12
N;N;N;N
REVEL
Benign
0.055
Sift
Benign
0.53
T;T;T;T
Sift4G
Benign
0.57
T;T;T;T
Vest4
0.40
MutPred
0.36
Loss of catalytic residue at I663 (P = 0.0069);.;.;.;
MVP
0.17
MPC
0.15
ClinPred
0.046
T
GERP RS
4.0
gMVP
0.15

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: rs538726706; hg19: chr6-112476121; API