9-113400480-C-T

Variant names:

• chr9-113400480-C-T
• rs818689
• NM_000031.6:c.-76+732G>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.-76+732G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,042 control chromosomes in the GnomAD database, including 2,532 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 0.18 (2532 hom., cov: 32)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 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.-76+732G>A		intron	N/A	NP_000022.3
	ALAD	NM_001003945.3		c.-155+732G>A		intron	N/A	NP_001003945.1
	ALAD	NM_001317745.2		c.-49+454G>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.-76+732G>A		intron	N/A	ENSP00000386284.3
	ALAD	ENST00000448137.5	TSL:4	c.-96+732G>A		intron	N/A	ENSP00000392748.1
	ALAD	ENST00000464749.5	TSL:4	n.73+732G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26865 AN: 151922 Hom.: 2535 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.162

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.177 AC: 26870 AN: 152042 Hom.: 2532 Cov.: 32 AF XY: 0.173 AC XY: 12869 AN XY: 74328

African (AFR) AF: 0.220 AC: 9132 AN: 41430

American (AMR) AF: 0.133 AC: 2041 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.0460 AC: 238 AN: 5176

South Asian (SAS) AF: 0.106 AC: 511 AN: 4818

European-Finnish (FIN) AF: 0.160 AC: 1690 AN: 10568

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12331 AN: 67964

Other (OTH) AF: 0.160 AC: 339 AN: 2114

Alfa AF: 0.176 Hom.: 9322

Bravo AF: 0.176

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.3
DANN	Benign	0.66
PhyloP100		0.18
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: rs818689; hg19: chr9-116162760;