18-6958610-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005559.4(LAMA1):c.7831A>G(p.Thr2611Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,948 control chromosomes in the GnomAD database, including 8,450 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2611P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.15 ( 4127 hom., cov: 33)

Exomes 𝑓: 0.038 ( 4323 hom. )

Consequence

LAMA1
NM_005559.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.164

Publications

17 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.8446317E-4).

BP6

Variant 18-6958610-T-C is Benign according to our data. Variant chr18-6958610-T-C is described in ClinVar as Benign. ClinVar VariationId is 1333053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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.7831A>G	p.Thr2611Ala	missense	Exon 55 of 63	NP_005550.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMA1	ENST00000389658.4	TSL:1 MANE Select	c.7831A>G	p.Thr2611Ala	missense	Exon 55 of 63	ENSP00000374309.3
LAMA1	ENST00000940203.1		c.7924A>G	p.Thr2642Ala	missense	Exon 56 of 64	ENSP00000610262.1
LAMA1	ENST00000940200.1		c.7831A>G	p.Thr2611Ala	missense	Exon 55 of 63	ENSP00000610259.1

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22117

AN:

152138

Hom.:

4105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.442

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0686

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0289

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0533

AC:

13411

AN:

251396

AF XY:

0.0447

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.0388

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0312

Gnomad OTH exome

AF:

0.0431

GnomAD4 exome

AF:

0.0380

AC:

55490

AN:

1461692

Hom.:

4323

Cov.:

AF XY:

0.0355

AC XY:

25778

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.456

AC:

15271

AN:

33464

American (AMR)

AF:

0.0418

AC:

1869

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

686

AN:

26132

East Asian (EAS)

AF:

0.000630

AC:

AN:

39696

South Asian (SAS)

AF:

0.00555

AC:

479

AN:

86258

European-Finnish (FIN)

AF:

0.0293

AC:

1565

AN:

53420

Middle Eastern (MID)

AF:

0.0648

AC:

374

AN:

5768

European-Non Finnish (NFE)

AF:

0.0287

AC:

31888

AN:

1111844

Other (OTH)

AF:

0.0552

AC:

3333

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2250

4500

6751

9001

11251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1402

2804

4206

5608

7010

<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

AF:

0.146

AC:

22186

AN:

152256

Hom.:

4127

Cov.:

AF XY:

0.142

AC XY:

10538

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.443

AC:

18379

AN:

41498

American (AMR)

AF:

0.0685

AC:

1048

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5188

South Asian (SAS)

AF:

0.00663

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0337

AC:

358

AN:

10618

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0289

AC:

1964

AN:

68030

Other (OTH)

AF:

0.107

AC:

227

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

723

1447

2170

2894

3617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0592

Hom.:

3505

Bravo

AF:

0.166

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0293

AC:

113

ESP6500AA

AF:

0.440

AC:

1940

ESP6500EA

AF:

0.0277

AC:

238

ExAC

AF:

0.0610

AC:

7402

EpiCase

AF:

0.0311

EpiControl

AF:

0.0335

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.5

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.036

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.069

MetaRNN

Benign

0.00028

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

PhyloP100

0.16

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.55

REVEL

Benign

0.23

Sift

Benign

0.39

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.0080

MPC

0.11

ClinPred

0.0028

GERP RS

-1.2

Varity_R

0.019

gMVP

0.40

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over