Genetic Variant NM_000031.6:c.262-139A>G (chr9-113391072-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.405

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ALAD	NM_000031.6 link	c.262-139A>G		intron_variant	Intron 4 of 11	ENST00000409155.8	NP_000022.3	P13716-1A0A140VJL9Q6ZMU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8 link	c.262-139A>G		intron_variant	Intron 4 of 11	1	NM_000031.6	ENSP00000386284.3		P13716-1

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88899

AN:

151882

Hom.:

26295

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.585

AC XY:

43462

AN XY:

74264

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

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

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