rs146868519

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001105206.3(LAMA4):c.2171G>A(p.Arg724Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000886 in 1,593,550 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R724G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 4 hom. )

Consequence

LAMA4
NM_001105206.3 missense, splice_region

Scores

Splicing: ADA: 0.00003214

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:10

Conservation

PhyloP100: 1.15

Publications

7 publications found

Variant links:

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

LAMA4 links:

ENSG00000237234 (HGNC:):

ENSG00000237234 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01657486).

BP6

Variant 6-112150513-C-T is Benign according to our data. Variant chr6-112150513-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44361.

BS2

High AC in GnomAd4 at 102 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMA4	NM_001105206.3	MANE Select	c.2171G>A	p.Arg724Lys	missense splice_region	Exon 17 of 39	NP_001098676.2	Q16363-1
LAMA4	NM_001105207.3		c.2150G>A	p.Arg717Lys	missense splice_region	Exon 17 of 39	NP_001098677.2	A0A0A0MTC7
LAMA4	NM_002290.5		c.2150G>A	p.Arg717Lys	missense splice_region	Exon 17 of 39	NP_002281.3	Q16363-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.2171G>A	p.Arg724Lys	missense splice_region	Exon 17 of 39	ENSP00000230538.7	Q16363-1
LAMA4	ENST00000389463.9	TSL:1	c.2150G>A	p.Arg717Lys	missense splice_region	Exon 17 of 39	ENSP00000374114.4	A0A0A0MTC7
LAMA4	ENST00000522006.5	TSL:1	c.2150G>A	p.Arg717Lys	missense splice_region	Exon 17 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000804

AC:

202

AN:

251370

AF XY:

0.000891

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000909

AC:

1310

AN:

1441380

Hom.:

Cov.:

AF XY:

0.000907

AC XY:

652

AN XY:

718520

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33050

American (AMR)

AF:

0.000761

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.000163

AC:

AN:

85858

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00110

AC:

1205

AN:

1093230

Other (OTH)

AF:

0.000720

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152170

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41438

American (AMR)

AF:

0.000262

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

68040

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000999

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000832

AC:

101

EpiCase

AF:

0.00131

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1JJ (4)

not provided (4)

not specified (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

LAMA4-related disorder (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.026

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.57

M_CAP

Benign

0.0069

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.94

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Benign

0.087

Sift

Benign

0.24

Sift4G

Benign

0.59

Vest4

0.13

MVP

0.21

MPC

0.12

ClinPred

0.017

GERP RS

4.2

PromoterAI

-0.020

Neutral

(source)

gMVP

0.25

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.010

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over