rs78871662

Variant names:

• chr6-112216481-A-G
• rs78871662
• NM_001105206.3:c.196-12T>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.196-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,553,406 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 33)
  • Exomes 𝑓: 0.020 (362 hom.)
• Consequence: LAMA4 NM_001105206.3 intron
• Scores: Splicing: ADA: 0.009147
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.782
• Publications: 2 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=-0.64).
• BP6: Variant 6-112216481-A-G is Benign according to our data. Variant chr6-112216481-A-G is described in ClinVar as Benign. ClinVar VariationId is 44354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0765 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	NM_001105206.3	MANE Select	c.196-12T>C		intron	N/A	NP_001098676.2
	LAMA4	NM_001105207.3		c.196-12T>C		intron	N/A	NP_001098677.2
	LAMA4	NM_002290.5		c.196-12T>C		intron	N/A	NP_002281.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.196-12T>C		intron	N/A	ENSP00000230538.7
	LAMA4	ENST00000389463.9	TSL:1	c.196-12T>C		intron	N/A	ENSP00000374114.4
	LAMA4	ENST00000522006.5	TSL:1	c.196-12T>C		intron	N/A	ENSP00000429488.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152220 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0189 AC: 4749 AN: 250622 AF XY: 0.0200

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0201 AC: 28231 AN: 1401068 Hom.: 362 Cov.: 24 AF XY: 0.0204 AC XY: 14275 AN XY: 701038

African (AFR) AF: 0.00573 AC: 185 AN: 32290

American (AMR) AF: 0.0148 AC: 661 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 822 AN: 25736

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39418

South Asian (SAS) AF: 0.0206 AC: 1751 AN: 84996

European-Finnish (FIN) AF: 0.0212 AC: 1130 AN: 53382

Middle Eastern (MID) AF: 0.0827 AC: 469 AN: 5672

European-Non Finnish (NFE) AF: 0.0207 AC: 21846 AN: 1056608

Other (OTH) AF: 0.0234 AC: 1363 AN: 58328

GnomAD4 genome AF: 0.0164 AC: 2505 AN: 152338 Hom.: 27 Cov.: 33 AF XY: 0.0167 AC XY: 1243 AN XY: 74488

African (AFR) AF: 0.00529 AC: 220 AN: 41580

American (AMR) AF: 0.0180 AC: 276 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 131 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4818

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0216 AC: 1468 AN: 68038

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0214 Hom.: 27

Bravo AF: 0.0155

Asia WGS AF: 0.0160 AC: 54 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Dilated cardiomyopathy 1JJ (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.63
PhyloP100		0.78
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0091
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: 48

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

Other links and lift over

dbSNP: rs78871662; hg19: chr6-112537682;