1-183103566-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_002293.4(LAMC1):c.657C>T(p.Asn219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,611,572 control chromosomes in the GnomAD database, including 14,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1020 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13365 hom.)
• Consequence: LAMC1 NM_002293.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0400

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-183103566-C-T is Benign according to our data. Variant chr1-183103566-C-T is described in ClinVar as [Benign]. Clinvar id is 1229870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC1	NM_002293.4	c.657C>T	p.Asn219=	synonymous_variant	2/28	ENST00000258341.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC1	ENST00000258341.5	c.657C>T	p.Asn219=	synonymous_variant	2/28	1	NM_002293.4	P1
LAMC1	ENST00000484114.2	c.-229C>T		5_prime_UTR_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15841 AN: 152134 Hom.: 1016 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.142 AC: 35290 AN: 249366 Hom.: 3136 AF XY: 0.140 AC XY: 18882 AN XY: 134636

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.127

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.129 AC: 187724 AN: 1459320 Hom.: 13365 Cov.: 34 AF XY: 0.130 AC XY: 94407 AN XY: 725676

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.0787

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.104 AC: 15855 AN: 152252 Hom.: 1020 Cov.: 32 AF XY: 0.107 AC XY: 7937 AN XY: 74452

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.0855

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.113

Alfa AF: 0.117 Hom.: 1445

Bravo AF: 0.111

Asia WGS AF: 0.145 AC: 504 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.113

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 04, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	8.9
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2296289; hg19: chr1-183072701; COSMIC: COSV51134952;