Variant 9-113386563-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000031.6(ALAD):c.*1737T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 152,100 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 51 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

ALAD
NM_000031.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.627

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 9-113386563-A-G is Benign according to our data. Variant chr9-113386563-A-G is described in ClinVar as [Benign]. Clinvar id is 913402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0193 (2935/152100) while in subpopulation NFE AF= 0.0291 (1980/67972). AF 95% confidence interval is 0.0281. There are 51 homozygotes in gnomad4. There are 1427 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6 linkuse as main transcript	c.*1737T>C		3_prime_UTR_variant	12/12	ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8 linkuse as main transcript	c.*1737T>C		3_prime_UTR_variant	12/12	1	NM_000031.6	P1	P13716-1
ALAD	ENST00000482847.5 linkuse as main transcript	n.3003T>C		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2935

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00510

Gnomad AMI

AF:

0.0474

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0291

Gnomad OTH

AF:

0.0115

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

GnomAD4 genome

AF:

0.0193

AC:

2935

AN:

152100

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1427

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00509

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0229

Gnomad4 FIN

AF:

0.0339

Gnomad4 NFE

AF:

0.0291

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0247

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Porphobilinogen synthase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.2

DANN

Benign

0.52

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