rs818689

chr9-113400480-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.-76+732G>A		intron_variant		ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.-76+732G>A		intron_variant		1	NM_000031.6	P1

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

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.0460

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.160

Alfa AF: 0.175 Hom.: 4061

Bravo AF: 0.176

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	7.3
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs818689; hg19: chr9-116162760;