rs543355

chr18-6958610-T-Cchr18-6958610-T-G

Variant summary

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

The NM_005559.4(LAMA1):c.7831A>G(p.Thr2611Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,948 control chromosomes in the GnomAD database, including 8,450 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2611I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (4127 hom., cov: 33)
  • Exomes 𝑓: 0.038 (4323 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.164

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8446317E-4).
• BP6: Variant 18-6958610-T-C is Benign according to our data. Variant chr18-6958610-T-C is described in ClinVar as [Benign]. Clinvar id is 1333053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA1	NM_005559.4	c.7831A>G	p.Thr2611Ala	missense_variant	55/63	ENST00000389658.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA1	ENST00000389658.4	c.7831A>G	p.Thr2611Ala	missense_variant	55/63	1	NM_005559.4	P1
LAMA1	ENST00000488064.5	n.1238A>G		non_coding_transcript_exon_variant	6/14	2
LAMA1	ENST00000488089.1	n.1408A>G		non_coding_transcript_exon_variant	2/3	2
LAMA1	ENST00000579014.5	n.8846A>G		non_coding_transcript_exon_variant	54/62	2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22117 AN: 152138 Hom.: 4105 Cov.: 33

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0686

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0533 AC: 13411 AN: 251396 Hom.: 1711 AF XY: 0.0447 AC XY: 6067 AN XY: 135872

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.0388

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0431

GnomAD4 exome AF: 0.0380 AC: 55490 AN: 1461692 Hom.: 4323 Cov.: 31 AF XY: 0.0355 AC XY: 25778 AN XY: 727158

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.0418

Gnomad4 ASJ exome AF: 0.0263

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.00555

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0287

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.146 AC: 22186 AN: 152256 Hom.: 4127 Cov.: 33 AF XY: 0.142 AC XY: 10538 AN XY: 74464

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.0685

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.0289

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0362 Hom.: 758

Bravo AF: 0.166

TwinsUK AF: 0.0305 AC: 113

ALSPAC AF: 0.0293 AC: 113

ESP6500AA AF: 0.440 AC: 1940

ESP6500EA AF: 0.0277 AC: 238

ExAC AF: 0.0610 AC: 7402

EpiCase AF: 0.0311

EpiControl AF: 0.0335

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	clinical testing	GeneDx	Jan 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	4.5
Dann	Benign	0.56
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.069	T;T
MetaRNN	Benign	0.00028	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.55	N;.
REVEL	Benign	0.23
Sift	Benign	0.39	T;.
Sift4G	Benign	0.48	T;.
Polyphen		0.0	B;.
Vest4		0.0080
MPC		0.11
ClinPred		0.0028	T
GERP RS		-1.2
Varity_R		0.019
gMVP		0.40

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: rs543355; hg19: chr18-6958609;