1-183125412-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002293.4(LAMC1):c.2663T>C(p.Leu888Pro) variant causes a missense change. The variant allele was found at a frequency of 0.566 in 1,613,112 control chromosomes in the GnomAD database, including 262,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.52 ( 21081 hom., cov: 31)

Exomes 𝑓: 0.57 ( 241133 hom. )

Consequence

LAMC1
NM_002293.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.47

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.3155422E-6).

BP6

Variant 1-183125412-T-C is Benign according to our data. Variant chr1-183125412-T-C is described in ClinVar as [Benign]. Clinvar id is 1290680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC1	NM_002293.4 link	c.2663T>C	p.Leu888Pro	missense_variant	Exon 15 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.2663T>C	p.Leu888Pro	missense_variant	Exon 15 of 28	1	NM_002293.4	ENSP00000258341.3		P11047
LAMC1	ENST00000466964.1 link	n.225T>C		non_coding_transcript_exon_variant	Exon 1 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78610

AN:

151888

Hom.:

21028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.618

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.648

Gnomad FIN

AF:

0.603

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.541

GnomAD3 exomes

AF:

0.580

AC:

145889

AN:

251378

Hom.:

43354

AF XY:

0.583

AC XY:

79266

AN XY:

135872

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 SAS exome

AF:

0.657

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.559

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

AF:

0.571

AC:

834916

AN:

1461106

Hom.:

241133

Cov.:

AF XY:

0.574

AC XY:

417360

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.362

Gnomad4 AMR exome

AF:

0.676

Gnomad4 ASJ exome

AF:

0.493

Gnomad4 EAS exome

AF:

0.617

Gnomad4 SAS exome

AF:

0.653

Gnomad4 FIN exome

AF:

0.593

Gnomad4 NFE exome

AF:

0.567

Gnomad4 OTH exome

AF:

0.571

GnomAD4 genome

AF:

0.518

AC:

78714

AN:

152006

Hom.:

21081

Cov.:

AF XY:

0.524

AC XY:

38954

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.374

Gnomad4 AMR

AF:

0.619

Gnomad4 ASJ

AF:

0.499

Gnomad4 EAS

AF:

0.610

Gnomad4 SAS

AF:

0.650

Gnomad4 FIN

AF:

0.603

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.547

Alfa

AF:

0.550

Hom.:

51781

Bravo

AF:

0.511

TwinsUK

AF:

0.569

AC:

2111

ALSPAC

AF:

0.566

AC:

2183

ESP6500AA

AF:

0.374

AC:

1650

ESP6500EA

AF:

0.570

AC:

4898

ExAC

AF:

0.572

AC:

69468

Asia WGS

AF:

0.643

AC:

2236

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.034

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.038

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.059

MetaRNN

Benign

0.0000053

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.8

PrimateAI

Benign

0.46

PROVEAN

Benign

5.2

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.072

MPC

0.14

ClinPred

0.0073

GERP RS

5.6

Varity_R

0.11

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over