6-112187553-G-C

Position:

• chr6-112187553-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001105206.3(LAMA4):​c.863C>G​(p.Ala288Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017960489).
• BP6: Variant 6-112187553-G-C is Benign according to our data. Variant chr6-112187553-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44410.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chr6-112187553-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.863C>G	p.Ala288Gly	missense_variant	8/39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.863C>G	p.Ala288Gly	missense_variant	8/39	1	NM_001105206.3	ENSP00000230538.7

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000506 AC: 127 AN: 251024 Hom.: 0 AF XY: 0.000509 AC XY: 69 AN XY: 135664

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000626

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000529 AC: 773 AN: 1461642 Hom.: 0 Cov.: 32 AF XY: 0.000553 AC XY: 402 AN XY: 727138

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000574

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74444

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	This variant is associated with the following publications: (PMID: 28798025) -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2013	The Ala281Gly variant in LAMA4 has not been reported in the literature nor previ ously detected by our laboratory. It is present in 3/8600 European American chro mosomes from a large population screened by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS/; dbSNP rs150084275). Alanine (Ala) at position 281 is not evolutionarily conserved and this variant (Ala281Gly) is present in another mammalian species, suggesting that it may be tolerated. Computational an alyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Ala281Gly variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of the Ala281Gly variant. -

Dilated cardiomyopathy 1JJ Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

LAMA4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2018

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0051	T;T;T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.74	T;.;.;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.63	N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.73	T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;.
Vest4		0.26
MVP		0.28
MPC		0.14
ClinPred		0.018	T
GERP RS		5.0
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs150084275; hg19: chr6-112508755;