rs769644598

chr18-6958544-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005559.4(LAMA1):c.7897G>A(p.Gly2633Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (1 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.737

Genes affected

LAMA1 (HGNC:6481): (laminin subunit alpha 1) This gene encodes one of the alpha 1 subunits of laminin. The laminins are a family of extracellular matrix glycoproteins that have a heterotrimeric structure consisting of an alpha, beta and gamma chain. These proteins make up a major component of the basement membrane and have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Mutations in this gene may be associated with Poretti-Boltshauser syndrome. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11948022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA1	NM_005559.4	c.7897G>A	p.Gly2633Arg	missense_variant	55/63	ENST00000389658.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA1	ENST00000389658.4	c.7897G>A	p.Gly2633Arg	missense_variant	55/63	1	NM_005559.4	P1
LAMA1	ENST00000488064.5	n.1304G>A		non_coding_transcript_exon_variant	6/14	2
LAMA1	ENST00000488089.1	n.1474G>A		non_coding_transcript_exon_variant	2/3	2
LAMA1	ENST00000579014.5	n.8912G>A		non_coding_transcript_exon_variant	54/62	2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251442 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000889 AC: 130 AN: 1461882 Hom.: 1 Cov.: 31 AF XY: 0.0000949 AC XY: 69 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000436

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2021	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2633 of the LAMA1 protein (p.Gly2633Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 435703). This variant has not been reported in the literature in individuals affected with LAMA1-related conditions. This variant is present in population databases (rs769644598, gnomAD 0.03%). -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	LAMA1: BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 06, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

The c.7897G>A (p.G2633R) alteration is located in exon 55 (coding exon 55) of the LAMA1 gene. This alteration results from a G to A substitution at nucleotide position 7897, causing the glycine (G) at amino acid position 2633 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	7.2
Dann	Benign	0.81
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.23
Sift	Benign	0.50	T;.
Sift4G	Benign	0.093	T;.
Polyphen		0.28	B;.
Vest4		0.21
MutPred		0.55		Loss of catalytic residue at S2635 (P = 0.0694);.;
MVP		0.72
MPC		0.15
ClinPred		0.064	T
GERP RS		4.6
Varity_R		0.055
gMVP		0.69

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: rs769644598; hg19: chr18-6958543; COSMIC: COSV67533139; COSMIC: COSV67533139;