1-183024246-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002293.4(LAMC1):c.418+112C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,058,494 control chromosomes in the GnomAD database, including 748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (323 hom., cov: 33)
  • Exomes 𝑓: 0.019 (425 hom.)
• Consequence: LAMC1 NM_002293.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.455

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-183024246-C-G is Benign according to our data. Variant chr1-183024246-C-G is described in ClinVar as [Benign]. Clinvar id is 1225486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC1	NM_002293.4	c.418+112C>G		intron_variant		ENST00000258341.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC1	ENST00000258341.5	c.418+112C>G		intron_variant		1	NM_002293.4	P1

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6865 AN: 152224 Hom.: 308 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0406

GnomAD4 exome AF: 0.0188 AC: 17043 AN: 906152 Hom.: 425 AF XY: 0.0206 AC XY: 9318 AN XY: 452094

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.000937

Gnomad4 SAS exome AF: 0.0775

Gnomad4 FIN exome AF: 0.00536

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0454 AC: 6914 AN: 152342 Hom.: 323 Cov.: 33 AF XY: 0.0445 AC XY: 3315 AN XY: 74496

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0797

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.00330 Hom.: 2

Bravo AF: 0.0481

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.7
Dann	Benign	0.64

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: rs111302764; hg19: chr1-182993381;