rs1800435

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:6

Conservation

PhyloP100: 2.03

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 16864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-113391611-C-G is described in Lovd as [Likely_benign].

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	P13716-1A0A140VJL9Q6ZMU0

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		P13716-1

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

GnomAD3 exomes

AF:

0.0827

AC:

20774

AN:

251162

Hom.:

1166

AF XY:

0.0896

AC XY:

12168

AN XY:

135792

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 SAS exome

AF:

0.146

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

Gnomad4 AFR exome

AF:

0.0133

Gnomad4 AMR exome

AF:

0.0427

Gnomad4 ASJ exome

AF:

0.226

Gnomad4 EAS exome

AF:

0.0578

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.0774

Gnomad4 NFE exome

AF:

0.0826

Gnomad4 OTH exome

AF:

0.0907

GnomAD4 genome

AF:

0.0626

AC:

9532

AN:

152286

Hom.:

416

Cov.:

AF XY:

0.0633

AC XY:

4716

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.0535

Gnomad4 ASJ

AF:

0.229

Gnomad4 EAS

AF:

0.0420

Gnomad4 SAS

AF:

0.150

Gnomad4 FIN

AF:

0.0719

Gnomad4 NFE

AF:

0.0798

Gnomad4 OTH

AF:

0.0687

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

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) -

Porphobilinogen synthase deficiency

Benign:2

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. -

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over