dbSNP rs4128458: LAD1:p.Lys323Glu (chr1-201386394-T-C) – 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.967A>G(p.Lys323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,518,574 control chromosomes in the GnomAD database, including 195,356 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 0.57 ( 26695 hom., cov: 32)

Exomes 𝑓: 0.49 ( 168661 hom. )

Consequence

LAD1
NM_005558.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

Publications

30 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=7.42325E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAD1	NM_005558.4 link	c.967A>G	p.Lys323Glu	missense_variant	Exon 3 of 10	ENST00000391967.7	NP_005549.2	O00515

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAD1	ENST00000391967.7 link	c.967A>G	p.Lys323Glu	missense_variant	Exon 3 of 10	1	NM_005558.4	ENSP00000375829.2		O00515
LAD1	ENST00000367313.4 link	c.1009A>G	p.Lys337Glu	missense_variant	Exon 3 of 10	1		ENSP00000356282.3		E9PDI4

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86921

AN:

151974

Hom.:

26662

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.567

Gnomad AMR

AF:

0.433

Gnomad ASJ

AF:

0.542

Gnomad EAS

AF:

0.508

Gnomad SAS

AF:

0.387

Gnomad FIN

AF:

0.478

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.583

GnomAD2 exomes

AF:

0.498

AC:

84869

AN:

170284

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.823

Gnomad AMR exome

AF:

0.359

Gnomad ASJ exome

AF:

0.537

Gnomad EAS exome

AF:

0.520

Gnomad FIN exome

AF:

0.499

Gnomad NFE exome

AF:

0.489

Gnomad OTH exome

AF:

0.479

GnomAD4 exome

AF:

0.493

AC:

673277

AN:

1366482

Hom.:

168661

Cov.:

AF XY:

0.489

AC XY:

327776

AN XY:

670058

show subpopulations

African (AFR)

AF:

0.829

AC:

25008

AN:

30156

American (AMR)

AF:

0.366

AC:

10377

AN:

28316

Ashkenazi Jewish (ASJ)

AF:

0.539

AC:

10700

AN:

19836

East Asian (EAS)

AF:

0.490

AC:

19070

AN:

38932

South Asian (SAS)

AF:

0.385

AC:

26578

AN:

69006

European-Finnish (FIN)

AF:

0.491

AC:

24416

AN:

49708

Middle Eastern (MID)

AF:

0.533

AC:

2775

AN:

5204

European-Non Finnish (NFE)

AF:

0.492

AC:

526077

AN:

1069124

Other (OTH)

AF:

0.503

AC:

28276

AN:

56200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

20593

41186

61780

82373

102966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15948

31896

47844

63792

79740

<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:

0.572

AC:

86997

AN:

152092

Hom.:

26695

Cov.:

AF XY:

0.565

AC XY:

42033

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.811

AC:

33673

AN:

41540

American (AMR)

AF:

0.433

AC:

6614

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

1880

AN:

3470

East Asian (EAS)

AF:

0.507

AC:

2613

AN:

5150

South Asian (SAS)

AF:

0.385

AC:

1861

AN:

4828

European-Finnish (FIN)

AF:

0.478

AC:

5066

AN:

10588

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.492

AC:

33381

AN:

67916

Other (OTH)

AF:

0.582

AC:

1227

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1778

3556

5335

7113

8891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.517

Hom.:

80324

Bravo

AF:

0.583

TwinsUK

AF:

0.498

AC:

1848

ALSPAC

AF:

0.491

AC:

1891

ESP6500AA

AF:

0.802

AC:

3531

ESP6500EA

AF:

0.489

AC:

4209

ExAC

AF:

0.480

AC:

55818

Asia WGS

AF:

0.487

AC:

1693

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.19

T;T

MetaRNN

Benign

7.4e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.038

MPC

0.15

ClinPred

0.0070

GERP RS

1.6

Varity_R

0.047

gMVP

0.051

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