9-113391072-T-C

Variant names:

• chr9-113391072-T-C
• rs2761016
• NM_000031.6:c.262-139A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• porphyria due to ALA dehydratase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.262-139A>G		intron_variant	Intron 4 of 11	ENST00000409155.8	NP_000022.3

Ensembl

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

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

African (AFR) AF: 0.652 AC: 16356 AN: 25070

American (AMR) AF: 0.685 AC: 22818 AN: 33322

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 10743 AN: 19518

East Asian (EAS) AF: 0.609 AC: 22098 AN: 36258

South Asian (SAS) AF: 0.447 AC: 28867 AN: 64594

European-Finnish (FIN) AF: 0.565 AC: 20731 AN: 36720

Middle Eastern (MID) AF: 0.505 AC: 1645 AN: 3260

European-Non Finnish (NFE) AF: 0.539 AC: 396904 AN: 735966

Other (OTH) AF: 0.546 AC: 24460 AN: 44834

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

African (AFR) AF: 0.651 AC: 26966 AN: 41450

American (AMR) AF: 0.658 AC: 10046 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1925 AN: 3472

East Asian (EAS) AF: 0.592 AC: 3044 AN: 5144

South Asian (SAS) AF: 0.452 AC: 2177 AN: 4814

European-Finnish (FIN) AF: 0.563 AC: 5953 AN: 10578

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36995 AN: 67954

Other (OTH) AF: 0.589 AC: 1241 AN: 2108

Alfa AF: 0.557 Hom.: 45281

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

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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