rs1299610144

Variant names:

• chr1-183023820-C-A
• rs1299610144
• NM_002293.4:c.104C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-183023820-C-A
• chr1-183023820-C-G
• chr1-183023820-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002293.4(LAMC1):​c.104C>A​(p.Ala35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAMC1 NM_002293.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35564476).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002293.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC1	NM_002293.4	MANE Select	c.104C>A	p.Ala35Glu	missense	Exon 1 of 28	NP_002284.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC1	ENST00000258341.5	TSL:1 MANE Select	c.104C>A	p.Ala35Glu	missense	Exon 1 of 28	ENSP00000258341.3	P11047
	LAMC1	ENST00000920737.1		c.104C>A	p.Ala35Glu	missense	Exon 1 of 29	ENSP00000590796.1
	LAMC1	ENST00000920738.1		c.104C>A	p.Ala35Glu	missense	Exon 1 of 28	ENSP00000590797.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419190 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 701206

African (AFR) AF: 0.00 AC: 0 AN: 32468

American (AMR) AF: 0.00 AC: 0 AN: 40984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38670

South Asian (SAS) AF: 0.00 AC: 0 AN: 79454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090176

Other (OTH) AF: 0.00 AC: 0 AN: 58306

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.82
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.23
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.48
MutPred		0.53		Loss of helix (P = 0.0033)
MVP		0.67
MPC		0.58
ClinPred		0.94	D
GERP RS		3.6
PromoterAI		-0.044	Neutral
Varity_R		0.35
gMVP		0.27
Mutation Taster		=71/29	polymorphism

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: rs1299610144; hg19: chr1-182992955;