rs20563

Positions:

• chr1-183116620-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (21113 hom., cov: 33)
  • Exomes 𝑓: 0.57 (240875 hom.)
• Consequence: LAMC1 NM_002293.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0150

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
LAMC1	NM_002293.4	c.1372A>G	p.Ile458Val	missense_variant	7/28	ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.1372A>G	p.Ile458Val	missense_variant	7/28	1	NM_002293.4	ENSP00000258341	P1
LAMC1	ENST00000479499.1	n.425A>G		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78685 AN: 151938 Hom.: 21060 Cov.: 33

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

GnomAD3 exomes AF: 0.580 AC: 145793 AN: 251182 Hom.: 43325 AF XY: 0.583 AC XY: 79206 AN XY: 135766

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: 833376 AN: 1458494 Hom.: 240875 Cov.: 37 AF XY: 0.574 AC XY: 416691 AN XY: 725772

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: 0.570

GnomAD4 genome AF: 0.518 AC: 78789 AN: 152056 Hom.: 21113 Cov.: 33 AF XY: 0.525 AC XY: 38985 AN XY: 74318

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.547

Alfa AF: 0.551 Hom.: 48640

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.54
DANN	Benign	0.51
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	0.0000055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.38
ClinPred		0.00093	T
GERP RS		-4.2
Varity_R		0.013
gMVP		0.18

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

Other links and lift over

dbSNP: rs20563; hg19: chr1-183085755; COSMIC: COSV51132249;