rs1805316

Positions:

• chr9-113390970-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000031.6(ALAD):​c.262-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,612,644 control chromosomes in the GnomAD database, including 5,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.082 (550 hom., cov: 33)
  • Exomes 𝑓: 0.081 (5320 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.83

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-113390970-A-G is Benign according to our data. Variant chr9-113390970-A-G is described in ClinVar as [Benign]. Clinvar id is 1227501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAD	NM_000031.6	c.262-37T>C		intron_variant		ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.262-37T>C		intron_variant		1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12450 AN: 152144 Hom.: 550 Cov.: 33

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0873

Gnomad OTH AF: 0.0587

GnomAD3 exomes AF: 0.0700 AC: 17481 AN: 249572 Hom.: 743 AF XY: 0.0703 AC XY: 9496 AN XY: 135068

Gnomad AFR exome AF: 0.0971

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0344

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0880

Gnomad OTH exome AF: 0.0642

GnomAD4 exome AF: 0.0815 AC: 118999 AN: 1460382 Hom.: 5320 Cov.: 34 AF XY: 0.0801 AC XY: 58155 AN XY: 726378

Gnomad4 AFR exome AF: 0.0939

Gnomad4 AMR exome AF: 0.0325

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0342

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.0881

Gnomad4 OTH exome AF: 0.0748

GnomAD4 genome AF: 0.0818 AC: 12457 AN: 152262 Hom.: 550 Cov.: 33 AF XY: 0.0818 AC XY: 6092 AN XY: 74448

Gnomad4 AFR AF: 0.0949

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.0873

Gnomad4 OTH AF: 0.0581

Alfa AF: 0.0848 Hom.: 184

Bravo AF: 0.0749

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.79
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1805316; hg19: chr9-116153250;