rs1139488

chr9-113391620-A-Gchr9-113391620-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000031.6(ALAD):c.168T>C(p.Tyr56=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,610,778 control chromosomes in the GnomAD database, including 108,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9990 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98426 hom.)
• Consequence: ALAD NM_000031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.120

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-113391620-A-G is Benign according to our data. Variant chr9-113391620-A-G is described in ClinVar as [Benign]. Clinvar id is 364653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-113391620-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.168T>C	p.Tyr56=	synonymous_variant	4/12	ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.168T>C	p.Tyr56=	synonymous_variant	4/12	1	NM_000031.6	P1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54313 AN: 151930 Hom.: 9974 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.347 AC: 86937 AN: 250642 Hom.: 15581 AF XY: 0.342 AC XY: 46424 AN XY: 135590

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.363 AC: 530214 AN: 1458730 Hom.: 98426 Cov.: 34 AF XY: 0.360 AC XY: 261336 AN XY: 725804

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.347

GnomAD4 genome AF: 0.358 AC: 54361 AN: 152048 Hom.: 9990 Cov.: 32 AF XY: 0.357 AC XY: 26558 AN XY: 74310

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.337

Alfa AF: 0.357 Hom.: 10581

Bravo AF: 0.348

Asia WGS AF: 0.344 AC: 1195 AN: 3478

EpiCase AF: 0.348

EpiControl AF: 0.351

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porphobilinogen synthase deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.2
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1139488; hg19: chr9-116153900; COSMIC: COSV52957876; COSMIC: COSV52957876;