rs1139488

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.168T>C(p.Tyr56Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,610,778 control chromosomes in the GnomAD database, including 108,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 9990 hom., cov: 32)

Exomes 𝑓: 0.36 ( 98426 hom. )

Consequence

ALAD
NM_000031.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.120

Publications

27 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=-0.54).

BP6

Variant 9-113391620-A-G is Benign according to our data. Variant chr9-113391620-A-G is described in ClinVar as Benign. ClinVar VariationId is 364653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.168T>C	p.Tyr56Tyr	synonymous_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.168T>C	p.Tyr56Tyr	synonymous_variant	Exon 4 of 12	1	NM_000031.6	ENSP00000386284.3		P13716-1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54313

AN:

151930

Hom.:

9974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.332

GnomAD2 exomes

AF:

0.347

AC:

86937

AN:

250642

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.329

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.421

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.363

AC:

530214

AN:

1458730

Hom.:

98426

Cov.:

AF XY:

0.360

AC XY:

261336

AN XY:

725804

show subpopulations

African (AFR)

AF:

0.320

AC:

10690

AN:

33430

American (AMR)

AF:

0.300

AC:

13424

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5537

AN:

26120

East Asian (EAS)

AF:

0.426

AC:

16885

AN:

39676

South Asian (SAS)

AF:

0.258

AC:

22252

AN:

86208

European-Finnish (FIN)

AF:

0.424

AC:

22597

AN:

53278

Middle Eastern (MID)

AF:

0.239

AC:

1380

AN:

5762

European-Non Finnish (NFE)

AF:

0.375

AC:

416524

AN:

1109282

Other (OTH)

AF:

0.347

AC:

20925

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

16299

32598

48896

65195

81494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13040

26080

39120

52160

65200

<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:

0.358

AC:

54361

AN:

152048

Hom.:

9990

Cov.:

AF XY:

0.357

AC XY:

26558

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.322

AC:

13356

AN:

41454

American (AMR)

AF:

0.346

AC:

5289

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

742

AN:

3470

East Asian (EAS)

AF:

0.465

AC:

2394

AN:

5150

South Asian (SAS)

AF:

0.261

AC:

1257

AN:

4822

European-Finnish (FIN)

AF:

0.427

AC:

4511

AN:

10570

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.379

AC:

25735

AN:

67974

Other (OTH)

AF:

0.337

AC:

712

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1815

3630

5444

7259

9074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

524

1048

1572

2096

2620

<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:

0.359

Hom.:

13061

Bravo

AF:

0.348

Asia WGS

AF:

0.344

AC:

1195

AN:

3478

EpiCase

AF:

0.348

EpiControl

AF:

0.351

ClinVar

Significance: Benign

Submissions summary: Benign: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

- -

Nov 10, 2018

GeneDx

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:2

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.2

(source)

DANN

Benign

0.49

PhyloP100

-0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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