rs2072021

Variant names:

• chr6-112191703-G-A
• rs2072021
• NM_001105206.3:c.651C>T
• LAMA4 p.Thr217Thr

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001105206.3(LAMA4):​c.651C>T​(p.Thr217Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,544 control chromosomes in the GnomAD database, including 29,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (7687 hom., cov: 32)
  • Exomes 𝑓: 0.15 (21733 hom.)
• Consequence: LAMA4 NM_001105206.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.43
• Publications: 20 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.07).
• BP6: Variant 6-112191703-G-A is Benign according to our data. Variant chr6-112191703-G-A is described in ClinVar as Benign. ClinVar VariationId is 44409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 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.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	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.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.651C>T	p.Thr217Thr	synonymous	Exon 6 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39717 AN: 151948 Hom.: 7671 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.189 AC: 47437 AN: 250782 AF XY: 0.186

Gnomad AFR exome AF: 0.556

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.151 AC: 220855 AN: 1461478 Hom.: 21733 Cov.: 33 AF XY: 0.153 AC XY: 111311 AN XY: 727058

African (AFR) AF: 0.558 AC: 18674 AN: 33460

American (AMR) AF: 0.138 AC: 6150 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4143 AN: 26132

East Asian (EAS) AF: 0.362 AC: 14344 AN: 39658

South Asian (SAS) AF: 0.244 AC: 21017 AN: 86248

European-Finnish (FIN) AF: 0.186 AC: 9935 AN: 53402

Middle Eastern (MID) AF: 0.173 AC: 995 AN: 5764

European-Non Finnish (NFE) AF: 0.122 AC: 135328 AN: 1111710

Other (OTH) AF: 0.170 AC: 10269 AN: 60384

GnomAD4 genome AF: 0.262 AC: 39786 AN: 152066 Hom.: 7687 Cov.: 32 AF XY: 0.264 AC XY: 19632 AN XY: 74336

African (AFR) AF: 0.541 AC: 22443 AN: 41450

American (AMR) AF: 0.170 AC: 2594 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3466

East Asian (EAS) AF: 0.289 AC: 1489 AN: 5150

South Asian (SAS) AF: 0.244 AC: 1172 AN: 4812

European-Finnish (FIN) AF: 0.196 AC: 2075 AN: 10584

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.131 AC: 8909 AN: 67998

Other (OTH) AF: 0.223 AC: 471 AN: 2112

Alfa AF: 0.181 Hom.: 10651

Bravo AF: 0.267

Asia WGS AF: 0.245 AC: 852 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.121

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.88
PhyloP100		-4.4
PromoterAI		-0.016	Neutral
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

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

Other links and lift over

dbSNP: rs2072021;

hg19: chr6-112512905;

COSMIC: COSV57894063;

COSMIC: COSV57894063;