chr1-183140367-T-A

Position:

• chr1-183140367-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000258341.5(LAMC1):​c.4474-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,232,940 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.023 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (78 hom.)
• Consequence: LAMC1 ENST00000258341.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.217

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]

LAMC1-AS1 (HGNC:52645): (LAMC1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-183140367-T-A is Benign according to our data. Variant chr1-183140367-T-A is described in ClinVar as [Benign]. Clinvar id is 1294851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC1	NM_002293.4	c.4474-37T>A		intron_variant		ENST00000258341.5	NP_002284.3
LAMC1-AS1	NR_149048.1	n.288+444A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.4474-37T>A		intron_variant		1	NM_002293.4	ENSP00000258341	P1
LAMC1-AS1	ENST00000457852.3	n.300+444A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3439 AN: 150136 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000641

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.000650

Gnomad OTH AF: 0.0218

GnomAD3 exomes AF: 0.00574 AC: 1184 AN: 206368 Hom.: 40 AF XY: 0.00400 AC XY: 450 AN XY: 112430

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000797

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00266 AC: 2875 AN: 1082670 Hom.: 78 Cov.: 13 AF XY: 0.00243 AC XY: 1344 AN XY: 552818

Gnomad4 AFR exome AF: 0.0724

Gnomad4 AMR exome AF: 0.00567

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000309

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.00661

GnomAD4 genome AF: 0.0230 AC: 3459 AN: 150270 Hom.: 141 Cov.: 32 AF XY: 0.0221 AC XY: 1619 AN XY: 73246

Gnomad4 AFR AF: 0.0762

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000427

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000635

Gnomad4 OTH AF: 0.0216

Alfa AF: 0.0101 Hom.: 8

Bravo AF: 0.0256

Asia WGS AF: 0.00606 AC: 21 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 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.26
DANN	Benign	0.73
BranchPoint Hunter		0.0

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: rs77860624; hg19: chr1-183109502;