Genetic Variant ALAD:c.-75-3509G>A (chr9-113397143-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000031.6(ALAD):c.-75-3509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,086 control chromosomes in the GnomAD database, including 2,890 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 2890 hom., cov: 31)

Exomes 𝑓: 0.036 ( 0 hom. )

Consequence

ALAD
NM_000031.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.415

Publications

9 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.-75-3509G>A		intron_variant	Intron 1 of 11	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8 link	c.-75-3509G>A		intron_variant	Intron 1 of 11	1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28404

AN:

151940

Hom.:

2894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.0411

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.164

GnomAD4 exome

AF:

0.0357

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0833

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.187

AC:

28411

AN:

152058

Hom.:

2890

Cov.:

AF XY:

0.183

AC XY:

13594

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.252

AC:

10440

AN:

41468

American (AMR)

AF:

0.135

AC:

2063

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

436

AN:

3468

East Asian (EAS)

AF:

0.0416

AC:

215

AN:

5168

South Asian (SAS)

AF:

0.106

AC:

509

AN:

4824

European-Finnish (FIN)

AF:

0.164

AC:

1740

AN:

10594

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.184

AC:

12516

AN:

67952

Other (OTH)

AF:

0.162

AC:

343

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1178

2356

3533

4711

5889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.175

Hom.:

4083

Bravo

AF:

0.187

Asia WGS

AF:

0.0550

AC:

193

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

3.2

(source)

DANN

Benign

0.35

PhyloP100

-0.41

PromoterAI

-0.0064

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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