rs818708

chr9-113387829-G-Achr9-113387829-G-Cchr9-113387829-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000031.6(ALAD):c.*471C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 203,248 control chromosomes in the GnomAD database, including 31,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (25945 hom., cov: 31)
  • Exomes 𝑓: 0.45 (5758 hom.)
• Consequence: ALAD NM_000031.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0670

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-113387829-G-A is Benign according to our data. Variant chr9-113387829-G-A is described in ClinVar as [Benign]. Clinvar id is 364632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.*471C>T		3_prime_UTR_variant	12/12	ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.*471C>T		3_prime_UTR_variant	12/12	1	NM_000031.6	P1
ALAD	ENST00000482847.5	n.1737C>T		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85202 AN: 151894 Hom.: 25895 Cov.: 31

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.454 AC: 23258 AN: 51236 Hom.: 5758 Cov.: 0 AF XY: 0.457 AC XY: 12183 AN XY: 26684

Gnomad4 AFR exome AF: 0.818

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.507

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.455

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.417

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.561 AC: 85297 AN: 152012 Hom.: 25945 Cov.: 31 AF XY: 0.557 AC XY: 41356 AN XY: 74300

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.551

Alfa AF: 0.480 Hom.: 28063

Bravo AF: 0.577

Asia WGS AF: 0.512 AC: 1782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.9
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs818708; hg19: chr9-116150109;