rs1413390

Variant names:

• chr1-183127499-G-A
• rs1413390
• NM_002293.4:c.3123+95G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LAMC1	NM_002293.4	c.3123+95G>A		intron_variant	Intron 17 of 27	ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.3123+95G>A		intron_variant	Intron 17 of 27	1	NM_002293.4	ENSP00000258341.3
LAMC1	ENST00000466964.1	n.685+95G>A		intron_variant	Intron 3 of 3	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

African (AFR) AF: 0.372 AC: 8762 AN: 23542

American (AMR) AF: 0.677 AC: 24871 AN: 36720

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 9885 AN: 19886

East Asian (EAS) AF: 0.619 AC: 22718 AN: 36714

South Asian (SAS) AF: 0.659 AC: 43403 AN: 65884

European-Finnish (FIN) AF: 0.595 AC: 29126 AN: 48968

Middle Eastern (MID) AF: 0.551 AC: 2107 AN: 3826

European-Non Finnish (NFE) AF: 0.572 AC: 396910 AN: 693602

Other (OTH) AF: 0.572 AC: 24957 AN: 43598

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

African (AFR) AF: 0.374 AC: 15518 AN: 41464

American (AMR) AF: 0.619 AC: 9451 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1729 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3165 AN: 5182

South Asian (SAS) AF: 0.651 AC: 3140 AN: 4822

European-Finnish (FIN) AF: 0.604 AC: 6396 AN: 10598

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37606 AN: 67982

Other (OTH) AF: 0.548 AC: 1159 AN: 2114

Alfa AF: 0.513 Hom.: 3202

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

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.87
DANN	Benign	0.66
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1413390; hg19: chr1-183096634; COSMIC: COSV107250176; COSMIC: COSV107250176;