rs2032568

Variant names:

• chr6-112136269-G-A
• rs2032568
• NM_001105206.3:c.3283-15C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-112136269-G-A
• chr6-112136269-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001105206.3(LAMA4):​c.3283-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,594,090 control chromosomes in the GnomAD database, including 436,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46181 hom., cov: 33)
  • Exomes 𝑓: 0.73 (389921 hom.)
• Consequence: LAMA4 NM_001105206.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.472
• Publications: 14 publications found

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]

LAMA4 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1JJ

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

LOC107986633 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-112136269-G-A is Benign according to our data. Variant chr6-112136269-G-A is described in ClinVar as Benign. ClinVar VariationId is 44375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.3283-15C>T		intron_variant	Intron 24 of 38	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.3283-15C>T		intron_variant	Intron 24 of 38	1	NM_001105206.3	ENSP00000230538.7

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117793 AN: 152052 Hom.: 46118 Cov.: 33

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.765

GnomAD2 exomes AF: 0.775 AC: 193138 AN: 249240 AF XY: 0.773

Gnomad AFR exome AF: 0.872

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.743

Gnomad NFE exome AF: 0.702

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.732 AC: 1056085 AN: 1441920 Hom.: 389921 Cov.: 28 AF XY: 0.736 AC XY: 528704 AN XY: 718520

African (AFR) AF: 0.867 AC: 28667 AN: 33078

American (AMR) AF: 0.866 AC: 38676 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19709 AN: 25984

East Asian (EAS) AF: 0.862 AC: 34058 AN: 39518

South Asian (SAS) AF: 0.858 AC: 73722 AN: 85894

European-Finnish (FIN) AF: 0.740 AC: 38615 AN: 52160

Middle Eastern (MID) AF: 0.707 AC: 4044 AN: 5722

European-Non Finnish (NFE) AF: 0.707 AC: 773985 AN: 1095192

Other (OTH) AF: 0.747 AC: 44609 AN: 59702

GnomAD4 genome AF: 0.775 AC: 117918 AN: 152170 Hom.: 46181 Cov.: 33 AF XY: 0.778 AC XY: 57880 AN XY: 74386

African (AFR) AF: 0.865 AC: 35913 AN: 41528

American (AMR) AF: 0.812 AC: 12414 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2630 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4480 AN: 5186

South Asian (SAS) AF: 0.871 AC: 4204 AN: 4824

European-Finnish (FIN) AF: 0.734 AC: 7759 AN: 10572

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 48033 AN: 67988

Other (OTH) AF: 0.768 AC: 1621 AN: 2112

Alfa AF: 0.735 Hom.: 23028

Bravo AF: 0.779

Asia WGS AF: 0.891 AC: 3095 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1JJ Benign:4

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.53
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2032568; hg19: chr6-112457471; COSMIC: COSV57893892;