rs1413390

Positions:

• chr1-183127499-G-A

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.3123+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,124,852 control chromosomes in the GnomAD database, including 184,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21130 hom., cov: 33)
  • Exomes 𝑓: 0.58 (163193 hom.)
• Consequence: LAMC1 NM_002293.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.407

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 (BayesDel_noAF=-0.92).
• BP6: Variant 1-183127499-G-A is Benign according to our data. Variant chr1-183127499-G-A is described in ClinVar as [Benign]. Clinvar id is 1238270.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.3123+95G>A		intron_variant		ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.3123+95G>A		intron_variant		1	NM_002293.4	ENSP00000258341	P1
LAMC1	ENST00000466964.1	n.685+95G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78728 AN: 151994 Hom.: 21077 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.542

GnomAD4 exome AF: 0.579 AC: 562739 AN: 972740 Hom.: 163193 AF XY: 0.582 AC XY: 287603 AN XY: 494578

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.497

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.595

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.572

GnomAD4 genome AF: 0.518 AC: 78832 AN: 152112 Hom.: 21130 Cov.: 33 AF XY: 0.525 AC XY: 39022 AN XY: 74378

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.498

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.548

Alfa AF: 0.518 Hom.: 3140

Bravo AF: 0.511

Asia WGS AF: 0.643 AC: 2235 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.87
DANN	Benign	0.66

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: rs1413390; hg19: chr1-183096634;