rs3734289

Variant names:

• chr6-112114070-A-C
• rs3734289
• NM_001105206.3:c.5326+6T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-112114070-A-C
• chr6-112114070-A-G
• chr6-112114070-A-T

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.5326+6T>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 0.259 in 1,610,248 control chromosomes in the GnomAD database, including 55,233 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 0.25 (4635 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50598 hom.)
• Consequence: LAMA4 NM_001105206.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001173
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.35
• Publications: 10 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: Illumina, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-112114070-A-C is Benign according to our data. Variant chr6-112114070-A-C is described in ClinVar as Benign. ClinVar VariationId is 44406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 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.5326+6T>G		splice_region intron	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.5305+6T>G		splice_region intron	N/A	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.5305+6T>G		splice_region intron	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.5326+6T>G		splice_region intron	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.5305+6T>G		splice_region intron	N/A	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.5305+6T>G		splice_region intron	N/A	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37689 AN: 151812 Hom.: 4636 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.238 AC: 59797 AN: 250990 AF XY: 0.236

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.260 AC: 378720 AN: 1458318 Hom.: 50598 Cov.: 35 AF XY: 0.256 AC XY: 185900 AN XY: 725702

African (AFR) AF: 0.233 AC: 7794 AN: 33408

American (AMR) AF: 0.187 AC: 8362 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 7704 AN: 26092

East Asian (EAS) AF: 0.310 AC: 12289 AN: 39664

South Asian (SAS) AF: 0.147 AC: 12644 AN: 86208

European-Finnish (FIN) AF: 0.216 AC: 11530 AN: 53400

Middle Eastern (MID) AF: 0.215 AC: 1237 AN: 5762

European-Non Finnish (NFE) AF: 0.272 AC: 301668 AN: 1108826

Other (OTH) AF: 0.257 AC: 15492 AN: 60274

GnomAD4 genome AF: 0.248 AC: 37710 AN: 151930 Hom.: 4635 Cov.: 32 AF XY: 0.243 AC XY: 18047 AN XY: 74256

African (AFR) AF: 0.238 AC: 9860 AN: 41456

American (AMR) AF: 0.207 AC: 3156 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1039 AN: 3464

East Asian (EAS) AF: 0.321 AC: 1649 AN: 5142

South Asian (SAS) AF: 0.158 AC: 761 AN: 4822

European-Finnish (FIN) AF: 0.204 AC: 2156 AN: 10558

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18257 AN: 67902

Other (OTH) AF: 0.262 AC: 550 AN: 2102

Alfa AF: 0.236 Hom.: 2899

Bravo AF: 0.251

EpiCase AF: 0.274

EpiControl AF: 0.275

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Dilated cardiomyopathy 1JJ (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.81
DANN	Benign	0.51
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3734289;

hg19: chr6-112435273;

COSMIC: COSV57893538;