chr18-7016662-AAT-A

Variant names:

• chr18-7016662-AAT-A
• rs587777680
• NM_005559.4:c.2816_2817delAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005559.4(LAMA1):​c.2816_2817delAT​(p.Tyr939LeufsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMA1 NM_005559.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.555
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-7016662-AAT-A is Pathogenic according to our data. Variant chr18-7016662-AAT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 144110.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA1	NM_005559.4	MANE Select	c.2816_2817delAT	p.Tyr939LeufsTer27	frameshift	Exon 21 of 63	NP_005550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA1	ENST00000389658.4	TSL:1 MANE Select	c.2816_2817delAT	p.Tyr939LeufsTer27	frameshift	Exon 21 of 63	ENSP00000374309.3
	LAMA1	ENST00000579014.5	TSL:2	n.3831_3832delAT		non_coding_transcript_exon	Exon 20 of 62

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 25, 2014

Dobyns Lab, Seattle Children's Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Aug 07, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs587777680; hg19: chr18-7016661;