Genetic Variant ALAD:c.-75-3185G>A (chr9-113396819-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.-75-3185G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,982 control chromosomes in the GnomAD database, including 2,481 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 0.17 ( 2465 hom., cov: 31)

Exomes 𝑓: 0.18 ( 16 hom. )

Consequence

ALAD
NM_000031.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.26

Publications

3 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=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.-75-3185G>A		intron_variant	Intron 1 of 11	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.-75-3185G>A		intron_variant	Intron 1 of 11	1	NM_000031.6	ENSP00000386284.3		P13716-1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26467

AN:

151846

Hom.:

2453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.166

GnomAD4 exome

AF:

0.178

AC:

181

AN:

1018

Hom.:

Cov.:

AF XY:

0.179

AC XY:

117

AN XY:

654

show subpopulations

African (AFR)

AF:

0.167

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.167

AC:

AN:

European-Finnish (FIN)

AF:

0.206

AC:

AN:

238

Middle Eastern (MID)

AF:

0.222

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

588

Other (OTH)

AF:

0.200

AC:

AN:

100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.174

AC:

26507

AN:

151964

Hom.:

2465

Cov.:

AF XY:

0.174

AC XY:

12965

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.192

AC:

7953

AN:

41418

American (AMR)

AF:

0.115

AC:

1754

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

914

AN:

3462

East Asian (EAS)

AF:

0.0252

AC:

130

AN:

5158

South Asian (SAS)

AF:

0.183

AC:

879

AN:

4816

European-Finnish (FIN)

AF:

0.235

AC:

2487

AN:

10576

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11890

AN:

67960

Other (OTH)

AF:

0.164

AC:

346

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1134

2268

3401

4535

5669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.171

Hom.:

4280

Bravo

AF:

0.165

Asia WGS

AF:

0.117

AC:

410

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.40

(source)

DANN

Benign

0.62

PhyloP100

-1.3

PromoterAI

-0.023

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

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9-113396819-C-T

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