rs2032568

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001105206.3(LAMA4):c.3283-15C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.472

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]

LAMA4 links:

LOC107986633 (HGNC:):

LOC107986633 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 44375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112136269-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.3283-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000230538.12
LOC107986633	XR_001744299.2 linkuse as main transcript	n.440-19051G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.3283-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes

AF:

0.775

AC:

117793

AN:

152052

Hom.:

46118

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.775

AC:

193138

AN:

249240

Hom.:

75707

AF XY:

0.773

AC XY:

104198

AN XY:

134824

show subpopulations

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 SAS exome

AF:

0.863

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.:

AF XY:

0.736

AC XY:

528704

AN XY:

718520

show subpopulations

Gnomad4 AFR exome

AF:

0.867

Gnomad4 AMR exome

AF:

0.866

Gnomad4 ASJ exome

AF:

0.759

Gnomad4 EAS exome

AF:

0.862

Gnomad4 SAS exome

AF:

0.858

Gnomad4 FIN exome

AF:

0.740

Gnomad4 NFE exome

AF:

0.707

Gnomad4 OTH exome

AF:

0.747

GnomAD4 genome

AF:

0.775

AC:

117918

AN:

152170

Hom.:

46181

Cov.:

AF XY:

0.778

AC XY:

57880

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.865

Gnomad4 AMR

AF:

0.812

Gnomad4 ASJ

AF:

0.757

Gnomad4 EAS

AF:

0.864

Gnomad4 SAS

AF:

0.871

Gnomad4 FIN

AF:

0.734

Gnomad4 NFE

AF:

0.706

Gnomad4 OTH

AF:

0.768

Alfa

AF:

0.736

Hom.:

20809

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Dilated cardiomyopathy 1JJ

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.85

DANN

Benign

0.53

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over