NM_000031.6:c.*471C>T

Variant names:

• chr9-113387829-G-A
• rs818708
• NM_000031.6:c.*471C>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: 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=-0.84).
• 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.

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.*471C>T		3_prime_UTR	Exon 12 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.*471C>T		3_prime_UTR	Exon 12 of 12	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.*471C>T		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.*471C>T		3_prime_UTR	Exon 12 of 12	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907374.1		c.*471C>T		3_prime_UTR	Exon 12 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.*471C>T		3_prime_UTR	Exon 12 of 12	ENSP00000577418.1

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

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	-0.84
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;