9-113387429-G-T

Variant names:

• chr9-113387429-G-T
• rs8177822
• NM_000031.6:c.*871C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000031.6(ALAD):​c.*871C>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 0.0321 in 152,286 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALAD NM_000031.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.427
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-113387429-G-T is Benign according to our data. Variant chr9-113387429-G-T is described in ClinVar as Benign. ClinVar VariationId is 364628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.063 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.*871C>A		3_prime_UTR	Exon 12 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.*871C>A		3_prime_UTR	Exon 12 of 12	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.*871C>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.*871C>A		3_prime_UTR	Exon 12 of 12	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907374.1		c.*871C>A		3_prime_UTR	Exon 12 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.*871C>A		3_prime_UTR	Exon 12 of 12	ENSP00000577418.1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4885 AN: 152168 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0311

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 30 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20

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) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0321 AC: 4887 AN: 152286 Hom.: 110 Cov.: 32 AF XY: 0.0314 AC XY: 2341 AN XY: 74464

African (AFR) AF: 0.0538 AC: 2236 AN: 41540

American (AMR) AF: 0.0193 AC: 295 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0691 AC: 333 AN: 4820

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1815 AN: 68036

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

Alfa AF: 0.0242 Hom.: 68

Bravo AF: 0.0317

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Porphobilinogen synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.083
DANN	Benign	0.65
PhyloP100		-0.43
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: rs8177822; hg19: chr9-116149709;