6-112175309-C-A

Variant names:

• chr6-112175309-C-A
• rs6917763
• NM_001105206.3:c.1357+4G>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.1357+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,590 control chromosomes in the GnomAD database, including 2,251 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 0.073 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.017 (1155 hom.)
• Consequence: LAMA4 NM_001105206.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002992
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.474
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-112175309-C-A is Benign according to our data. Variant chr6-112175309-C-A is described in ClinVar as Benign. ClinVar VariationId is 44343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 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.1357+4G>T		splice_region intron	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.1336+4G>T		splice_region intron	N/A	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.1336+4G>T		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.1357+4G>T		splice_region intron	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.1336+4G>T		splice_region intron	N/A	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.1336+4G>T		splice_region intron	N/A	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11074 AN: 152108 Hom.: 1093 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0272 AC: 6834 AN: 251202 AF XY: 0.0237

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0165 AC: 24170 AN: 1461364 Hom.: 1155 Cov.: 32 AF XY: 0.0159 AC XY: 11530 AN XY: 726994

African (AFR) AF: 0.238 AC: 7968 AN: 33448

American (AMR) AF: 0.0215 AC: 961 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 650 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0103 AC: 884 AN: 86228

European-Finnish (FIN) AF: 0.00706 AC: 377 AN: 53418

Middle Eastern (MID) AF: 0.0759 AC: 424 AN: 5584

European-Non Finnish (NFE) AF: 0.0102 AC: 11298 AN: 1111780

Other (OTH) AF: 0.0266 AC: 1608 AN: 60358

GnomAD4 genome AF: 0.0729 AC: 11100 AN: 152226 Hom.: 1096 Cov.: 33 AF XY: 0.0704 AC XY: 5243 AN XY: 74452

African (AFR) AF: 0.225 AC: 9334 AN: 41488

American (AMR) AF: 0.0417 AC: 638 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4820

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10616

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 762 AN: 68018

Other (OTH) AF: 0.0634 AC: 134 AN: 2114

Alfa AF: 0.0283 Hom.: 718

Bravo AF: 0.0833

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0158

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		-0.47
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs6917763; hg19: chr6-112496511;