18-6942147-A-G

Position:

chr18-6942147-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005559.4(LAMA1):c.9160T>C(p.Phe3054Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LAMA1
NM_005559.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03758067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA1	NM_005559.4 linkuse as main transcript	c.9160T>C	p.Phe3054Leu	missense_variant	63/63	ENST00000389658.4	NP_005550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMA1	ENST00000389658.4 linkuse as main transcript	c.9160T>C	p.Phe3054Leu	missense_variant	63/63	1	NM_005559.4	ENSP00000374309	P1
LAMA1	ENST00000488064.5 linkuse as main transcript	n.2567T>C		non_coding_transcript_exon_variant	14/14	2
LAMA1	ENST00000492048.5 linkuse as main transcript	n.2048T>C		non_coding_transcript_exon_variant	7/7	2
LAMA1	ENST00000579014.5 linkuse as main transcript	n.10175T>C		non_coding_transcript_exon_variant	62/62	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Poretti-Boltshauser syndrome (MIM#615960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated Laminin G-like 5 domain (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.4

DANN

Benign

0.80

DEOGEN2

Benign

0.013

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.38

M_CAP

Benign

0.0079

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.20

REVEL

Benign

0.032

Sift

Benign

0.71

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.045

MutPred

0.34

Loss of catalytic residue at S3057 (P = 0.1396);

MVP

0.21

MPC

0.13

ClinPred

0.031

GERP RS

1.8

Varity_R

0.034

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over