rs117433399

Variant names:

• chr18-6982520-T-C
• rs117433399
• NM_005559.4:c.5867A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005559.4(LAMA1):​c.5867A>G​(p.Asn1956Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,174 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1956D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: LAMA1 NM_005559.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.386
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057021976).
• BP6: Variant 18-6982520-T-C is Benign according to our data. Variant chr18-6982520-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377115.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005559.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA1	NM_005559.4	MANE Select	c.5867A>G	p.Asn1956Ser	missense	Exon 41 of 63	NP_005550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA1	ENST00000389658.4	TSL:1 MANE Select	c.5867A>G	p.Asn1956Ser	missense	Exon 41 of 63	ENSP00000374309.3
	LAMA1	ENST00000940203.1		c.5960A>G	p.Asn1987Ser	missense	Exon 42 of 64	ENSP00000610262.1
	LAMA1	ENST00000940200.1		c.5867A>G	p.Asn1956Ser	missense	Exon 41 of 63	ENSP00000610259.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00149 AC: 374 AN: 251492 AF XY: 0.00144

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00225 AC: 3289 AN: 1461876 Hom.: 5 Cov.: 32 AF XY: 0.00224 AC XY: 1631 AN XY: 727244

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00271 AC: 3011 AN: 1111996

Other (OTH) AF: 0.00210 AC: 127 AN: 60396

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74490

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.00216 AC: 33 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00223 Hom.: 3

Bravo AF: 0.00171

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00314

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	-	1	LAMA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.64
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.39
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.033
Sift	Benign	0.25	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.041
MVP		0.19
MPC		0.085
ClinPred		0.0018	T
GERP RS		-1.4
Varity_R		0.031
gMVP		0.053
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs117433399; hg19: chr18-6982519;