dbSNP rs797045184: LAMA1:c.6345+3G>C (chr18-6977724-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_005559.4(LAMA1):c.6345+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LAMA1
NM_005559.4 splice_region, intron

Scores

Splicing: ADA: 0.9994

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.996

Publications

1 publications found

Variant links:

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)

LAMA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 18-6977724-C-G is Pathogenic according to our data. Variant chr18-6977724-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 209991.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA1	NM_005559.4 link	c.6345+3G>C		splice_region_variant, intron_variant	Intron 44 of 62	ENST00000389658.4	NP_005550.2	P25391

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA1	ENST00000389658.4 link	c.6345+3G>C		splice_region_variant, intron_variant	Intron 44 of 62	1	NM_005559.4	ENSP00000374309.3		P25391
LAMA1	ENST00000579014.5 link	n.7360+3G>C		splice_region_variant, intron_variant	Intron 43 of 61	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

Pathogenic:1

Nov 25, 2014

Dobyns Lab, Seattle Children's Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: 3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over