dbSNP rs12088790: LAD1:p.Leu243Pro (chr1-201386633-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005558.4(LAD1):c.728T>C(p.Leu243Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,614,078 control chromosomes in the GnomAD database, including 4,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 2369 hom., cov: 33)

Exomes 𝑓: 0.035 ( 2566 hom. )

Consequence

LAD1
NM_005558.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.84

Publications

12 publications found

Variant links:

Genes affected

LAD1 (HGNC:6472): (ladinin 1) The protein encoded by this gene may be an anchoring filament that is a component of basement membranes. It may contribute to the stability of the association of the epithelial layers with the underlying mesenchyme. [provided by RefSeq, Jul 2008]

LAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038383007).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAD1	NM_005558.4 link	c.728T>C	p.Leu243Pro	missense_variant	Exon 3 of 10	ENST00000391967.7	NP_005549.2	O00515

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAD1	ENST00000391967.7 link	c.728T>C	p.Leu243Pro	missense_variant	Exon 3 of 10	1	NM_005558.4	ENSP00000375829.2	O00515
LAD1	ENST00000367313.4 link	c.770T>C	p.Leu257Pro	missense_variant	Exon 3 of 10	1		ENSP00000356282.3	E9PDI4
LAD1	ENST00000632743.1 link	c.*214T>C		downstream_gene_variant		4		ENSP00000487828.1	A0A0J9YW63
LAD1	ENST00000631576.1 link	c.*178T>C		downstream_gene_variant		4		ENSP00000488829.1	A0A0J9YYF6

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17238

AN:

152088

Hom.:

2355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.326

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0851

Gnomad EAS

AF:

0.0314

Gnomad SAS

AF:

0.0310

Gnomad FIN

AF:

0.0342

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0746

GnomAD2 exomes

AF:

0.0505

AC:

12676

AN:

251160

AF XY:

0.0451

show subpopulations

Gnomad AFR exome

AF:

0.339

Gnomad AMR exome

AF:

0.0282

Gnomad ASJ exome

AF:

0.0780

Gnomad EAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0262

Gnomad OTH exome

AF:

0.0436

GnomAD4 exome

AF:

0.0346

AC:

50544

AN:

1461872

Hom.:

2566

Cov.:

AF XY:

0.0337

AC XY:

24526

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.335

AC:

11224

AN:

33476

American (AMR)

AF:

0.0318

AC:

1422

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0789

AC:

2063

AN:

26136

East Asian (EAS)

AF:

0.0279

AC:

1107

AN:

39700

South Asian (SAS)

AF:

0.0327

AC:

2822

AN:

86258

European-Finnish (FIN)

AF:

0.0326

AC:

1742

AN:

53416

Middle Eastern (MID)

AF:

0.0777

AC:

448

AN:

5768

European-Non Finnish (NFE)

AF:

0.0239

AC:

26603

AN:

1111998

Other (OTH)

AF:

0.0515

AC:

3113

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2804

5608

8413

11217

14021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1186

2372

3558

4744

5930

<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:

0.114

AC:

17284

AN:

152206

Hom.:

2369

Cov.:

AF XY:

0.112

AC XY:

8328

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.327

AC:

13547

AN:

41476

American (AMR)

AF:

0.0524

AC:

801

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

295

AN:

3468

East Asian (EAS)

AF:

0.0313

AC:

162

AN:

5178

South Asian (SAS)

AF:

0.0313

AC:

151

AN:

4830

European-Finnish (FIN)

AF:

0.0342

AC:

363

AN:

10620

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1764

AN:

68014

Other (OTH)

AF:

0.0752

AC:

159

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

639

1279

1918

2558

3197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.0535

Hom.:

2468

Bravo

AF:

0.126

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.330

AC:

1454

ESP6500EA

AF:

0.0292

AC:

251

ExAC

AF:

0.0554

AC:

6728

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0298

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.12

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.038

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.17

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.0

N;.

PhyloP100

-1.8

PrimateAI

Benign

0.27

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.010

Sift

Benign

0.43

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0040

B;B

Vest4

0.035

MPC

0.17

ClinPred

0.0035

GERP RS

0.80

Varity_R

0.026

gMVP

0.024

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over