rs1139488

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000031.6(ALAD):c.168T>C(p.Tyr56Tyr) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.120

Variant links:

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 links:

ALAD (HGNC:):

ALAD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ALAD	NM_000031.6 linkuse as main transcript	c.168T>C	p.Tyr56Tyr	synonymous_variant	4/12	ENST00000409155.8	NP_000022.3	P13716-1A0A140VJL9Q6ZMU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8 linkuse as main transcript	c.168T>C	p.Tyr56Tyr	synonymous_variant	4/12	1	NM_000031.6	ENSP00000386284.3		P13716-1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54313

AN:

151930

Hom.:

9974

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.360

AC XY:

261336

AN XY:

725804

show subpopulations

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.:

AF XY:

0.357

AC XY:

26558

AN XY:

74310

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over