chr1-183023890-C-T

Variant names:

• chr1-183023890-C-T
• rs10911194
• NM_002293.4:c.174C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002293.4(LAMC1):​c.174C>T​(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,612,232 control chromosomes in the GnomAD database, including 244,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19600 hom., cov: 33)
  • Exomes 𝑓: 0.55 (224517 hom.)
• Consequence: LAMC1 NM_002293.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.296
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-183023890-C-T is Benign according to our data. Variant chr1-183023890-C-T is described in CliVar as Benign. Clinvar id is 1179935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183023890-C-T is described in CliVar as Benign. Clinvar id is 1179935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183023890-C-T is described in CliVar as Benign. Clinvar id is 1179935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183023890-C-T is described in CliVar as Benign. Clinvar id is 1179935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183023890-C-T is described in CliVar as Benign. Clinvar id is 1179935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.296 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC1	NM_002293.4	c.174C>T	p.Ala58Ala	synonymous_variant	Exon 1 of 28	ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.174C>T	p.Ala58Ala	synonymous_variant	Exon 1 of 28	1	NM_002293.4	ENSP00000258341.3

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75664 AN: 151868 Hom.: 19550 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.562 AC: 138332 AN: 246000 AF XY: 0.565

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.623

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.551 AC: 804782 AN: 1460246 Hom.: 224517 Cov.: 58 AF XY: 0.554 AC XY: 402166 AN XY: 726368

African (AFR) AF: 0.346 AC: 11565 AN: 33462

American (AMR) AF: 0.662 AC: 29580 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12098 AN: 26100

East Asian (EAS) AF: 0.619 AC: 24554 AN: 39676

South Asian (SAS) AF: 0.638 AC: 55020 AN: 86204

European-Finnish (FIN) AF: 0.579 AC: 30392 AN: 52492

Middle Eastern (MID) AF: 0.498 AC: 2875 AN: 5768

European-Non Finnish (NFE) AF: 0.545 AC: 605617 AN: 1111530

Other (OTH) AF: 0.548 AC: 33081 AN: 60338

GnomAD4 genome AF: 0.498 AC: 75765 AN: 151986 Hom.: 19600 Cov.: 33 AF XY: 0.506 AC XY: 37591 AN XY: 74274

African (AFR) AF: 0.358 AC: 14833 AN: 41486

American (AMR) AF: 0.597 AC: 9132 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1635 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3131 AN: 5114

South Asian (SAS) AF: 0.637 AC: 3072 AN: 4820

European-Finnish (FIN) AF: 0.594 AC: 6285 AN: 10580

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35931 AN: 67914

Other (OTH) AF: 0.518 AC: 1094 AN: 2112

Alfa AF: 0.513 Hom.: 15909

Bravo AF: 0.491

Asia WGS AF: 0.638 AC: 2218 AN: 3478

EpiCase AF: 0.536

EpiControl AF: 0.532

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.30
PromoterAI		-0.061	Neutral
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: rs10911194; hg19: chr1-182993025; COSMIC: COSV51159812;