rs71543223

Variant names:

• chr6-112187567-GT-TG
• rs71543223
• NM_001105206.3:c.848_849delACinsCA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001105206.3(LAMA4):​c.848_849delACinsCA​(p.Asp283Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D283H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.24
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 6-112187567-GT-TG is Benign according to our data. Variant chr6-112187567-GT-TG is described in ClinVar as Benign. ClinVar VariationId is 224939.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	NM_001105206.3	MANE Select	c.848_849delACinsCA	p.Asp283Ala	missense	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.827_828delACinsCA	p.Asp276Ala	missense	N/A	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.827_828delACinsCA	p.Asp276Ala	missense	N/A	NP_002281.3	Q16363-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.848_849delACinsCA	p.Asp283Ala	missense	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.827_828delACinsCA	p.Asp276Ala	missense	N/A	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.827_828delACinsCA	p.Asp276Ala	missense	N/A	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated cardiomyopathy 1JJ (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71543223; hg19: chr6-112508769;