rs2228083

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000031.6(ALAD):c.414C>T(p.Asn138Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 1,613,900 control chromosomes in the GnomAD database, including 5,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 559 hom., cov: 33)

Exomes 𝑓: 0.080 ( 4938 hom. )

Consequence

ALAD
NM_000031.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.590

Publications

16 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 9-113390660-G-A is Benign according to our data. Variant chr9-113390660-G-A is described in ClinVar as Benign. ClinVar VariationId is 364650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.414C>T	p.Asn138Asn	synonymous_variant	Exon 6 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.414C>T	p.Asn138Asn	synonymous_variant	Exon 6 of 12	1	NM_000031.6	ENSP00000386284.3		P13716-1

Frequencies

GnomAD3 genomes

AF:

0.0812

AC:

12358

AN:

152186

Hom.:

558

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0872

Gnomad AMI

AF:

0.0727

Gnomad AMR

AF:

0.0609

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.0931

Gnomad SAS

AF:

0.0682

Gnomad FIN

AF:

0.0879

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0838

Gnomad OTH

AF:

0.0822

GnomAD2 exomes

AF:

0.0746

AC:

18643

AN:

249910

AF XY:

0.0747

show subpopulations

Gnomad AFR exome

AF:

0.0862

Gnomad AMR exome

AF:

0.0397

Gnomad ASJ exome

AF:

0.0319

Gnomad EAS exome

AF:

0.0935

Gnomad FIN exome

AF:

0.0916

Gnomad NFE exome

AF:

0.0823

Gnomad OTH exome

AF:

0.0792

GnomAD4 exome

AF:

0.0798

AC:

116664

AN:

1461596

Hom.:

4938

Cov.:

AF XY:

0.0795

AC XY:

57789

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0850

AC:

2846

AN:

33474

American (AMR)

AF:

0.0426

AC:

1905

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

824

AN:

26126

East Asian (EAS)

AF:

0.0652

AC:

2589

AN:

39686

South Asian (SAS)

AF:

0.0691

AC:

5956

AN:

86242

European-Finnish (FIN)

AF:

0.0902

AC:

4815

AN:

53370

Middle Eastern (MID)

AF:

0.0376

AC:

217

AN:

5768

European-Non Finnish (NFE)

AF:

0.0835

AC:

92802

AN:

1111864

Other (OTH)

AF:

0.0780

AC:

4710

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

6905

13809

20714

27618

34523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3354

6708

10062

13416

16770

<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:

0.0812

AC:

12372

AN:

152304

Hom.:

559

Cov.:

AF XY:

0.0801

AC XY:

5965

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0872

AC:

3627

AN:

41576

American (AMR)

AF:

0.0608

AC:

930

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

119

AN:

3472

East Asian (EAS)

AF:

0.0937

AC:

484

AN:

5164

South Asian (SAS)

AF:

0.0683

AC:

330

AN:

4832

European-Finnish (FIN)

AF:

0.0879

AC:

933

AN:

10612

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0838

AC:

5699

AN:

68024

Other (OTH)

AF:

0.0823

AC:

174

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

584

1169

1753

2338

2922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0793

Hom.:

789

Bravo

AF:

0.0775

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.0761

EpiControl

AF:

0.0695

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Porphobilinogen synthase deficiency

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.5

(source)

DANN

Benign

0.62

PhyloP100

-0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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