rs818706

Variant names:

• chr9-113386350-C-T
• rs818706
• NM_000031.6:c.*1950G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-113386350-C-T
• chr9-113386350-C-A

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.*1950G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 152,208 control chromosomes in the GnomAD database, including 52,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52367 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ALAD NM_000031.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24
• Publications: 6 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 9-113386350-C-T is Benign according to our data. Variant chr9-113386350-C-T is described in ClinVar as Benign. ClinVar VariationId is 364618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.*1950G>A		3_prime_UTR	Exon 12 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.*1950G>A		3_prime_UTR	Exon 12 of 12	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.*1950G>A		3_prime_UTR	Exon 11 of 11	NP_001304674.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.*1950G>A		3_prime_UTR	Exon 12 of 12	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907374.1		c.*1950G>A		3_prime_UTR	Exon 12 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.*1950G>A		3_prime_UTR	Exon 12 of 12	ENSP00000577418.1

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125787 AN: 152090 Hom.: 52322 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.827

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.827 AC: 125892 AN: 152208 Hom.: 52367 Cov.: 33 AF XY: 0.824 AC XY: 61336 AN XY: 74436

African (AFR) AF: 0.875 AC: 36322 AN: 41514

American (AMR) AF: 0.716 AC: 10941 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3022 AN: 3472

East Asian (EAS) AF: 0.638 AC: 3311 AN: 5186

South Asian (SAS) AF: 0.795 AC: 3835 AN: 4822

European-Finnish (FIN) AF: 0.865 AC: 9169 AN: 10602

Middle Eastern (MID) AF: 0.873 AC: 255 AN: 292

European-Non Finnish (NFE) AF: 0.832 AC: 56557 AN: 68012

Other (OTH) AF: 0.828 AC: 1749 AN: 2112

Alfa AF: 0.829 Hom.: 192769

Bravo AF: 0.816

Asia WGS AF: 0.741 AC: 2578 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Porphobilinogen synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.66
DANN	Benign	0.35
PhyloP100		-1.2
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: rs818706; hg19: chr9-116148630;