rs144738522

Positions:

• chr18-7023208-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005559.4(LAMA1):​c.2657C>T​(p.Ala886Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,613,534 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.24

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]

LAMA1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 18-7023208-G-A is Benign according to our data. Variant chr18-7023208-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr18-7023208-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA1	NM_005559.4	c.2657C>T	p.Ala886Val	missense_variant	19/63	ENST00000389658.4	NP_005550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA1	ENST00000389658.4	c.2657C>T	p.Ala886Val	missense_variant	19/63	1	NM_005559.4	ENSP00000374309.3
LAMA1	ENST00000579014.5	n.3672C>T		non_coding_transcript_exon_variant	18/62	2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00209 AC: 526 AN: 251144 Hom.: 2 AF XY: 0.00217 AC XY: 295 AN XY: 135766

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00314 AC: 4584 AN: 1461286 Hom.: 10 Cov.: 31 AF XY: 0.00303 AC XY: 2201 AN XY: 726916

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74440

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00315 Hom.: 1

Bravo AF: 0.00246

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LAMA1: BP4, BS2 -

LAMA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
Polyphen		0.91	P
Vest4		0.59
MVP		0.79
MPC		0.40
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 6
DS_DL_spliceai		0.32		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144738522; hg19: chr18-7023207;