9-113391072-T-C

Position:

• chr9-113391072-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000031.6(ALAD):​c.262-139A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,151,544 control chromosomes in the GnomAD database, including 177,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26342 hom., cov: 33)
  • Exomes 𝑓: 0.54 (150837 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.405

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-113391072-T-C is Benign according to our data. Variant chr9-113391072-T-C is described in ClinVar as [Benign]. Clinvar id is 1242889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.262-139A>G		intron_variant		ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.262-139A>G		intron_variant		1	NM_000031.6	P1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88899 AN: 151882 Hom.: 26295 Cov.: 33

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.545 AC: 544622 AN: 999542 Hom.: 150837 AF XY: 0.541 AC XY: 272141 AN XY: 502872

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.685

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.609

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.565

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.546

GnomAD4 genome AF: 0.586 AC: 89008 AN: 152002 Hom.: 26342 Cov.: 33 AF XY: 0.585 AC XY: 43462 AN XY: 74264

Gnomad4 AFR AF: 0.651

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.589

Alfa AF: 0.551 Hom.: 32289

Bravo AF: 0.599

Asia WGS AF: 0.543 AC: 1888 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.89

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: rs2761016; hg19: chr9-116153352; COSMIC: COSV52958250; COSMIC: COSV52958250;