rs12961939

Positions:

• chr18-6997819-A-C
• chr18-6997819-A-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.4729T>G​(p.Ser1577Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,613,506 control chromosomes in the GnomAD database, including 49,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3828 hom., cov: 33)
  • Exomes 𝑓: 0.24 (45497 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.43

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=0.009468079).
• BP6: Variant 18-6997819-A-C is Benign according to our data. Variant chr18-6997819-A-C is described in ClinVar as [Benign]. Clinvar id is 803471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA1	NM_005559.4	c.4729T>G	p.Ser1577Ala	missense_variant	33/63	ENST00000389658.4	NP_005550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA1	ENST00000389658.4	c.4729T>G	p.Ser1577Ala	missense_variant	33/63	1	NM_005559.4	ENSP00000374309	P1
LAMA1	ENST00000579014.5	n.5744T>G		non_coding_transcript_exon_variant	32/62	2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32638 AN: 152114 Hom.: 3824 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.0575

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.204 AC: 51254 AN: 251450 Hom.: 6044 AF XY: 0.205 AC XY: 27799 AN XY: 135904

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.0511

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.242 AC: 353748 AN: 1461274 Hom.: 45497 Cov.: 34 AF XY: 0.238 AC XY: 173324 AN XY: 726960

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.0585

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.215 AC: 32658 AN: 152232 Hom.: 3828 Cov.: 33 AF XY: 0.210 AC XY: 15607 AN XY: 74436

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.0573

Gnomad4 SAS AF: 0.0997

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.228

Alfa AF: 0.251 Hom.: 12760

Bravo AF: 0.209

TwinsUK AF: 0.273 AC: 1011

ALSPAC AF: 0.265 AC: 1020

ESP6500AA AF: 0.149 AC: 658

ESP6500EA AF: 0.269 AC: 2311

ExAC AF: 0.203 AC: 24583

Asia WGS AF: 0.105 AC: 362 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.273

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.019	D
Sift4G	Benign	0.14	T
Polyphen		0.36	B
Vest4		0.14
MPC		0.16
ClinPred		0.040	T
GERP RS		4.2
Varity_R		0.11
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: rs12961939; hg19: chr18-6997818; COSMIC: COSV67538361;