rs1800435

Variant names:

Variant summary

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

The NM_000031.6(ALAD):c.177G>C(p.Lys59Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,613,738 control chromosomes in the GnomAD database, including 6,502 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 416 hom., cov: 32)

Exomes 𝑓: 0.085 ( 6086 hom. )

Consequence

ALAD
NM_000031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 2.03

Publications

108 publications found

Variant links:

Genes affected

ALAD (HGNC:395): (aminolevulinate dehydratase) The ALAD enzyme is composed of 8 identical subunits and catalyzes the condensation of 2 molecules of delta-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). ALAD catalyzes the second step in the porphyrin and heme biosynthetic pathway; zinc is essential for enzymatic activity. ALAD enzymatic activity is inhibited by lead and a defect in the ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ALAD Gene-Disease associations (from GenCC):

porphyria due to ALA dehydratase deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ALAD 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=0.0013033152).

BP6

Variant 9-113391611-C-G is Benign according to our data. Variant chr9-113391611-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 16864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.177G>C	p.Lys59Asn	missense_variant	Exon 4 of 12	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8 link	c.177G>C	p.Lys59Asn	missense_variant	Exon 4 of 12	1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes

AF:

0.0627

AC:

9536

AN:

152168

Hom.:

417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0536

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.0419

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0719

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0827

AC:

20774

AN:

251162

AF XY:

0.0896

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0401

Gnomad ASJ exome

AF:

0.222

Gnomad EAS exome

AF:

0.0362

Gnomad FIN exome

AF:

0.0776

Gnomad NFE exome

AF:

0.0842

Gnomad OTH exome

AF:

0.0942

GnomAD4 exome

AF:

0.0855

AC:

124884

AN:

1461452

Hom.:

6086

Cov.:

AF XY:

0.0878

AC XY:

63842

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.0133

AC:

444

AN:

33476

American (AMR)

AF:

0.0427

AC:

1911

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

5904

AN:

26130

East Asian (EAS)

AF:

0.0578

AC:

2295

AN:

39700

South Asian (SAS)

AF:

0.143

AC:

12289

AN:

86236

European-Finnish (FIN)

AF:

0.0774

AC:

4129

AN:

53350

Middle Eastern (MID)

AF:

0.104

AC:

598

AN:

5768

European-Non Finnish (NFE)

AF:

0.0826

AC:

91840

AN:

1111690

Other (OTH)

AF:

0.0907

AC:

5474

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5789

11579

17368

23158

28947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3442

6884

10326

13768

17210

<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:

0.0626

AC:

9532

AN:

152286

Hom.:

416

Cov.:

AF XY:

0.0633

AC XY:

4716

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0141

AC:

585

AN:

41564

American (AMR)

AF:

0.0535

AC:

819

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

795

AN:

3472

East Asian (EAS)

AF:

0.0420

AC:

217

AN:

5166

South Asian (SAS)

AF:

0.150

AC:

725

AN:

4822

European-Finnish (FIN)

AF:

0.0719

AC:

763

AN:

10618

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0798

AC:

5426

AN:

68026

Other (OTH)

AF:

0.0687

AC:

145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

450

899

1349

1798

2248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0885

Hom.:

598

Bravo

AF:

0.0581

TwinsUK

AF:

0.0734

AC:

272

ALSPAC

AF:

0.0815

AC:

314

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0834

AC:

717

ExAC

AF:

0.0825

AC:

10021

Asia WGS

AF:

0.0840

AC:

293

AN:

3478

EpiCase

AF:

0.0876

EpiControl

AF:

0.0896

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Porphobilinogen synthase deficiency

Benign:3

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mar 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:3

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25239657, 16909025, 9593628, 11342419, 11071662) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALAD*1/ALAD*2 POLYMORPHISM

Pathogenic:1

Oct 01, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.6

N;.

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

4.9

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;.

Vest4

0.038

MutPred

0.17

Loss of methylation at K59 (P = 0.0155);.;

MPC

0.44

ClinPred

0.0039

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.50

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over