rs8177804

Positions:

• chr9-113391109-C-T

Variant summary

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

The ENST00000409155.8(ALAD):​c.262-176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,240 control chromosomes in the GnomAD database, including 1,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.14 (1628 hom., cov: 33)
• Consequence: ALAD ENST00000409155.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.943

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 9-113391109-C-T is Benign according to our data. Variant chr9-113391109-C-T is described in ClinVar as [Benign]. Clinvar id is 1238193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAD	NM_000031.6	c.262-176G>A		intron_variant		ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.262-176G>A		intron_variant		1	NM_000031.6	ENSP00000386284	P1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21486 AN: 152122 Hom.: 1628 Cov.: 33

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.141 AC: 21491 AN: 152240 Hom.: 1628 Cov.: 33 AF XY: 0.141 AC XY: 10482 AN XY: 74414

Gnomad4 AFR AF: 0.0959

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.147

Alfa AF: 0.162 Hom.: 1539

Bravo AF: 0.133

Asia WGS AF: 0.151 AC: 526 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.58

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: rs8177804; hg19: chr9-116153389; COSMIC: COSV52958257; COSMIC: COSV52958257;