6-112201692-A-C

Variant names:

• chr6-112201692-A-C
• rs79008328
• NM_001105206.3:c.423-4T>G

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.423-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,612,792 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 33)
  • Exomes 𝑓: 0.010 (145 hom.)
• Consequence: LAMA4 NM_001105206.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005193
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.630
• Publications: 3 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-112201692-A-C is Benign according to our data. Variant chr6-112201692-A-C is described in ClinVar as Benign. ClinVar VariationId is 44385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	NM_001105206.3	MANE Select	c.423-4T>G		splice_region intron	N/A	NP_001098676.2
	LAMA4	NM_001105207.3		c.423-4T>G		splice_region intron	N/A	NP_001098677.2
	LAMA4	NM_002290.5		c.423-4T>G		splice_region intron	N/A	NP_002281.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.423-4T>G		splice_region intron	N/A	ENSP00000230538.7
	LAMA4	ENST00000389463.9	TSL:1	c.423-4T>G		splice_region intron	N/A	ENSP00000374114.4
	LAMA4	ENST00000522006.5	TSL:1	c.423-4T>G		splice_region intron	N/A	ENSP00000429488.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2797 AN: 152228 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0122 AC: 3054 AN: 250746 AF XY: 0.0120

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00695

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0105 AC: 15265 AN: 1460446 Hom.: 145 Cov.: 31 AF XY: 0.0103 AC XY: 7512 AN XY: 726640

African (AFR) AF: 0.0425 AC: 1421 AN: 33422

American (AMR) AF: 0.0115 AC: 514 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 649 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00324 AC: 279 AN: 86240

European-Finnish (FIN) AF: 0.00707 AC: 377 AN: 53344

Middle Eastern (MID) AF: 0.0689 AC: 397 AN: 5760

European-Non Finnish (NFE) AF: 0.00968 AC: 10758 AN: 1110854

Other (OTH) AF: 0.0144 AC: 870 AN: 60316

GnomAD4 genome AF: 0.0184 AC: 2801 AN: 152346 Hom.: 43 Cov.: 33 AF XY: 0.0185 AC XY: 1376 AN XY: 74494

African (AFR) AF: 0.0383 AC: 1591 AN: 41580

American (AMR) AF: 0.0171 AC: 262 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10624

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 701 AN: 68024

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0168 Hom.: 25

Bravo AF: 0.0207

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0148

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Dilated cardiomyopathy 1JJ (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.4
DANN	Benign	0.75
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.044
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: rs79008328; hg19: chr6-112522893;