rs20563

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002293.4(LAMC1):c.1372A>G(p.Ile458Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,610,550 control chromosomes in the GnomAD database, including 261,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21113 hom., cov: 33)

Exomes 𝑓: 0.57 ( 240875 hom. )

Consequence

LAMC1
NM_002293.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0150

Publications

66 publications found

Variant links:

Genes affected

LAMC1 (HGNC:6492): (laminin subunit gamma 1) 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, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have 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 gamma chain isoform laminin, gamma 1. The gamma 1 chain, formerly thought to be a beta chain, contains structural domains similar to beta chains, however, lacks the short alpha region separating domains I and II. The structural organization of this gene also suggested that it had diverged considerably from the beta chain genes. Embryos of transgenic mice in which both alleles of the gamma 1 chain gene were inactivated by homologous recombination, lacked basement membranes, indicating that laminin, gamma 1 chain is necessary for laminin heterotrimer assembly. It has been inferred by analogy with the strikingly similar 3' UTR sequence in mouse laminin gamma 1 cDNA, that multiple polyadenylation sites are utilized in human to generate the 2 different sized mRNAs (5.5 and 7.5 kb) seen on Northern analysis. [provided by RefSeq, Aug 2011]

LAMC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.4817606E-6).

BP6

Variant 1-183116620-A-G is Benign according to our data. Variant chr1-183116620-A-G is described in ClinVar as Benign. ClinVar VariationId is 1238059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC1	NM_002293.4 link	c.1372A>G	p.Ile458Val	missense_variant	Exon 7 of 28	ENST00000258341.5	NP_002284.3	P11047Q6NVY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5 link	c.1372A>G	p.Ile458Val	missense_variant	Exon 7 of 28	1	NM_002293.4	ENSP00000258341.3		P11047
LAMC1	ENST00000479499.1 link	n.425A>G		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78685

AN:

151938

Hom.:

21060

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.618

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.611

Gnomad SAS

AF:

0.648

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.541

GnomAD2 exomes

AF:

0.580

AC:

145793

AN:

251182

AF XY:

0.583

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.680

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.621

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.559

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

AF:

0.571

AC:

833376

AN:

1458494

Hom.:

240875

Cov.:

AF XY:

0.574

AC XY:

416691

AN XY:

725772

show subpopulations

African (AFR)

AF:

0.362

AC:

12085

AN:

33424

American (AMR)

AF:

0.676

AC:

30202

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.493

AC:

12872

AN:

26114

East Asian (EAS)

AF:

0.617

AC:

24497

AN:

39678

South Asian (SAS)

AF:

0.653

AC:

56217

AN:

86106

European-Finnish (FIN)

AF:

0.593

AC:

31647

AN:

53394

Middle Eastern (MID)

AF:

0.541

AC:

3117

AN:

5766

European-Non Finnish (NFE)

AF:

0.567

AC:

628346

AN:

1109040

Other (OTH)

AF:

0.570

AC:

34393

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

16031

32061

48092

64122

80153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17548

35096

52644

70192

87740

<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:

0.518

AC:

78789

AN:

152056

Hom.:

21113

Cov.:

AF XY:

0.525

AC XY:

38985

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.374

AC:

15524

AN:

41494

American (AMR)

AF:

0.619

AC:

9450

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1729

AN:

3466

East Asian (EAS)

AF:

0.611

AC:

3167

AN:

5180

South Asian (SAS)

AF:

0.651

AC:

3141

AN:

4826

European-Finnish (FIN)

AF:

0.604

AC:

6356

AN:

10530

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.553

AC:

37599

AN:

67976

Other (OTH)

AF:

0.547

AC:

1155

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1929

3858

5786

7715

9644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.547

Hom.:

89823

Bravo

AF:

0.511

TwinsUK

AF:

0.569

AC:

2108

ALSPAC

AF:

0.566

AC:

2182

ESP6500AA

AF:

0.374

AC:

1650

ESP6500EA

AF:

0.570

AC:

4898

ExAC

AF:

0.572

AC:

69475

Asia WGS

AF:

0.643

AC:

2235

AN:

3478

EpiCase

AF:

0.564

EpiControl

AF:

0.560

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.54

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.038

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.067

MetaRNN

Benign

0.0000055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.6

PhyloP100

-0.015

PrimateAI

Benign

0.37

PROVEAN

Benign

0.78

REVEL

Benign

0.065

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.021

MPC

0.38

ClinPred

0.00093

GERP RS

-4.2

Varity_R

0.013

gMVP

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over