6-112172687-A-T

Variant names:

• chr6-112172687-A-T
• rs3752579
• NM_001105206.3:c.1475T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001105206.3(LAMA4):​c.1475T>A​(p.Leu492His) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,613,914 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 5.57
• Publications: 13 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, Illumina, Labcorp Genetics (formerly Invitae)
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006751567).
• BP6: Variant 6-112172687-A-T is Benign according to our data. Variant chr6-112172687-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44347.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00125 (1823/1461704) while in subpopulation EAS AF = 0.0281 (1114/39698). AF 95% confidence interval is 0.0267. There are 32 homozygotes in GnomAdExome4. There are 880 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 180 AD gene.

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.1475T>A	p.Leu492His	missense	Exon 12 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.1454T>A	p.Leu485His	missense	Exon 12 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.1454T>A	p.Leu485His	missense	Exon 12 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.1475T>A	p.Leu492His	missense	Exon 12 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.1454T>A	p.Leu485His	missense	Exon 12 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.1454T>A	p.Leu485His	missense	Exon 12 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0153

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00314 AC: 789 AN: 251350 AF XY: 0.00249

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00125 AC: 1823 AN: 1461704 Hom.: 32 Cov.: 33 AF XY: 0.00121 AC XY: 880 AN XY: 727140

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.0131 AC: 585 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0281 AC: 1114 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5656

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111986

Other (OTH) AF: 0.000845 AC: 51 AN: 60370

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74414

African (AFR) AF: 0.0000963 AC: 4 AN: 41520

American (AMR) AF: 0.00556 AC: 85 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5164

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000949 Hom.: 1

Bravo AF: 0.00181

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not specified (6)
-	-	2	Dilated cardiomyopathy 1JJ (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.2	T
PhyloP100		5.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.62
MVP		0.46
MPC		0.61
ClinPred		0.11	T
GERP RS		5.5
gMVP		0.71
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3752579; hg19: chr6-112493889; COSMIC: COSV100037688;