rs566655

Positions:

• chr18-7034509-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.2021A>C​(p.Asn674Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 1,613,588 control chromosomes in the GnomAD database, including 38,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N674N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3236 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34828 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.538

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=0.002455771).
• BP6: Variant 18-7034509-T-G is Benign according to our data. Variant chr18-7034509-T-G is described in ClinVar as [Benign]. Clinvar id is 803473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA1	NM_005559.4	c.2021A>C	p.Asn674Thr	missense_variant	14/63	ENST00000389658.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA1	ENST00000389658.4	c.2021A>C	p.Asn674Thr	missense_variant	14/63	1	NM_005559.4	P1
LAMA1	ENST00000579014.5	n.3036A>C		non_coding_transcript_exon_variant	13/62	2

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30412 AN: 152002 Hom.: 3228 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.197 AC: 49418 AN: 251384 Hom.: 5325 AF XY: 0.198 AC XY: 26970 AN XY: 135872

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.214 AC: 313395 AN: 1461468 Hom.: 34828 Cov.: 34 AF XY: 0.213 AC XY: 155145 AN XY: 727072

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.200 AC: 30438 AN: 152120 Hom.: 3236 Cov.: 33 AF XY: 0.199 AC XY: 14763 AN XY: 74352

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.226

Alfa AF: 0.225 Hom.: 10109

Bravo AF: 0.197

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.228 AC: 880

ESP6500AA AF: 0.164 AC: 724

ESP6500EA AF: 0.231 AC: 1987

ExAC AF: 0.193 AC: 23404

Asia WGS AF: 0.115 AC: 399 AN: 3476

EpiCase AF: 0.237

EpiControl AF: 0.233

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	0.49	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.75	P
Vest4		0.10
MPC		0.12
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.072
gMVP		0.45

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: rs566655; hg19: chr18-7034508; COSMIC: COSV67531785; COSMIC: COSV67531785;