18-6985271-C-T

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.5626G>A(p.Ala1876Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,613,800 control chromosomes in the GnomAD database, including 45,019 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A1876P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2926 hom., cov: 33)

Exomes 𝑓: 0.23 ( 42093 hom. )

Consequence

LAMA1
NM_005559.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0480

Publications

32 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=0.0038636029).

BP6

Variant 18-6985271-C-T is Benign according to our data. Variant chr18-6985271-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA1	NM_005559.4	MANE Select	c.5626G>A	p.Ala1876Thr	missense	Exon 39 of 63	NP_005550.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMA1	ENST00000389658.4	TSL:1 MANE Select	c.5626G>A	p.Ala1876Thr	missense	Exon 39 of 63	ENSP00000374309.3
LAMA1	ENST00000940203.1		c.5719G>A	p.Ala1907Thr	missense	Exon 40 of 64	ENSP00000610262.1
LAMA1	ENST00000940200.1		c.5626G>A	p.Ala1876Thr	missense	Exon 39 of 63	ENSP00000610259.1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26752

AN:

152080

Hom.:

2928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0459

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.199

GnomAD2 exomes

AF:

0.195

AC:

48968

AN:

251422

AF XY:

0.200

show subpopulations

Gnomad AFR exome

AF:

0.0415

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.264

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.234

AC:

341884

AN:

1461602

Hom.:

42093

Cov.:

AF XY:

0.232

AC XY:

168977

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.0391

AC:

1310

AN:

33476

American (AMR)

AF:

0.113

AC:

5051

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6698

AN:

26132

East Asian (EAS)

AF:

0.165

AC:

6547

AN:

39698

South Asian (SAS)

AF:

0.148

AC:

12753

AN:

86252

European-Finnish (FIN)

AF:

0.207

AC:

11032

AN:

53420

Middle Eastern (MID)

AF:

0.210

AC:

1211

AN:

5754

European-Non Finnish (NFE)

AF:

0.255

AC:

283704

AN:

1111770

Other (OTH)

AF:

0.225

AC:

13578

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

14502

29004

43507

58009

72511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9404

18808

28212

37616

47020

<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:

0.176

AC:

26742

AN:

152198

Hom.:

2926

Cov.:

AF XY:

0.172

AC XY:

12763

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0458

AC:

1902

AN:

41536

American (AMR)

AF:

0.165

AC:

2529

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

852

AN:

3470

East Asian (EAS)

AF:

0.186

AC:

959

AN:

5168

South Asian (SAS)

AF:

0.144

AC:

697

AN:

4828

European-Finnish (FIN)

AF:

0.197

AC:

2082

AN:

10584

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.252

AC:

17156

AN:

67996

Other (OTH)

AF:

0.198

AC:

418

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1061

2123

3184

4246

5307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.222

Hom.:

14561

Bravo

AF:

0.168

TwinsUK

AF:

0.265

AC:

983

ALSPAC

AF:

0.251

AC:

967

ESP6500AA

AF:

0.0511

AC:

225

ESP6500EA

AF:

0.256

AC:

2201

ExAC

AF:

0.194

AC:

23568

Asia WGS

AF:

0.167

AC:

581

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.261

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

PhyloP100

-0.048

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.065

Sift

Benign

0.094

Sift4G

Benign

0.12

Polyphen

0.15

Vest4

0.016

MPC

0.11

ClinPred

0.0030

GERP RS

-0.59

Varity_R

0.037

gMVP

0.053

Mutation Taster

=98/2

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