1-183023599-A-G

Position:

• chr1-183023599-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.-118A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 748,908 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (322 hom., cov: 30)
  • Exomes 𝑓: 0.016 (172 hom.)
• Consequence: LAMC1 NM_002293.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31

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=-0.81).
• BP6: Variant 1-183023599-A-G is Benign according to our data. Variant chr1-183023599-A-G is described in ClinVar as [Benign]. Clinvar id is 1282385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
LAMC1	NM_002293.4	c.-118A>G		5_prime_UTR_variant	1/28	ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.-118A>G		5_prime_UTR_variant	1/28	1	NM_002293.4	ENSP00000258341.3

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6856 AN: 151710 Hom.: 308 Cov.: 30

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.00342

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0403

GnomAD4 exome AF: 0.0156 AC: 9290 AN: 597090 Hom.: 172 Cov.: 8 AF XY: 0.0157 AC XY: 4496 AN XY: 286388

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.0747

Gnomad4 FIN exome AF: 0.00646

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0455 AC: 6903 AN: 151818 Hom.: 322 Cov.: 30 AF XY: 0.0446 AC XY: 3308 AN XY: 74212

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00196

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.00342

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0399

Alfa AF: 0.00495 Hom.: 1

Bravo AF: 0.0482

Asia WGS AF: 0.0500 AC: 174 AN: 3424

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 13, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.4
DANN	Benign	0.65

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: rs138247851; hg19: chr1-182992734;