rs818708

Variant names:

• chr9-113387829-G-A
• rs818708
• NM_000031.6:c.*471C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-113387829-G-A
• chr9-113387829-G-C
• chr9-113387829-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0670
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 364632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.*471C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.*471C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_000031.6	ENSP00000386284.3
ALAD	ENST00000482847.5	n.1737C>T		non_coding_transcript_exon_variant	Exon 12 of 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

African (AFR) AF: 0.818 AC: 1565 AN: 1914

American (AMR) AF: 0.447 AC: 1778 AN: 3974

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 529 AN: 1044

East Asian (EAS) AF: 0.608 AC: 1985 AN: 3266

South Asian (SAS) AF: 0.455 AC: 3128 AN: 6876

European-Finnish (FIN) AF: 0.391 AC: 659 AN: 1686

Middle Eastern (MID) AF: 0.531 AC: 86 AN: 162

European-Non Finnish (NFE) AF: 0.417 AC: 12354 AN: 29644

Other (OTH) AF: 0.440 AC: 1174 AN: 2670

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

African (AFR) AF: 0.810 AC: 33612 AN: 41488

American (AMR) AF: 0.491 AC: 7492 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1768 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3213 AN: 5176

South Asian (SAS) AF: 0.468 AC: 2252 AN: 4808

European-Finnish (FIN) AF: 0.402 AC: 4245 AN: 10552

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30982 AN: 67954

Other (OTH) AF: 0.551 AC: 1162 AN: 2108

Alfa AF: 0.486 Hom.: 36793

Bravo AF: 0.577

Asia WGS AF: 0.512 AC: 1782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porphobilinogen synthase deficiency Benign:1

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.69
PhyloP100		0.067
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs818708; hg19: chr9-116150109;