chr9-113397143-C-T

Variant names:

• chr9-113397143-C-T
• rs818684
• NM_000031.6:c.-75-3509G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000031.6(ALAD):​c.-75-3509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,086 control chromosomes in the GnomAD database, including 2,890 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (2890 hom., cov: 31)
  • Exomes 𝑓: 0.036 (0 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.415
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.-75-3509G>A		intron	N/A	NP_000022.3
	ALAD	NM_001003945.3		c.-154-3509G>A		intron	N/A	NP_001003945.1
	ALAD	NM_001317745.2		c.-48-3509G>A		intron	N/A	NP_001304674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.-75-3509G>A		intron	N/A	ENSP00000386284.3
	ALAD	ENST00000452726.1	TSL:3	c.-146G>A		5_prime_UTR	Exon 1 of 3	ENSP00000415737.1
	ALAD	ENST00000448137.5	TSL:4	c.-49+935G>A		intron	N/A	ENSP00000392748.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28404 AN: 151940 Hom.: 2894 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0411

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.164

GnomAD4 exome AF: 0.0357 AC: 1 AN: 28 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.187 AC: 28411 AN: 152058 Hom.: 2890 Cov.: 31 AF XY: 0.183 AC XY: 13594 AN XY: 74344

African (AFR) AF: 0.252 AC: 10440 AN: 41468

American (AMR) AF: 0.135 AC: 2063 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3468

East Asian (EAS) AF: 0.0416 AC: 215 AN: 5168

South Asian (SAS) AF: 0.106 AC: 509 AN: 4824

European-Finnish (FIN) AF: 0.164 AC: 1740 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12516 AN: 67952

Other (OTH) AF: 0.162 AC: 343 AN: 2114

Alfa AF: 0.175 Hom.: 4083

Bravo AF: 0.187

Asia WGS AF: 0.0550 AC: 193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.35
PhyloP100		-0.41
PromoterAI		-0.0064	Neutral
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: rs818684; hg19: chr9-116159423;