9-113388911-A-G

Variant names:

• chr9-113388911-A-G
• rs1805313
• NM_000031.6:c.931+66T>C

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.931+66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,611,600 control chromosomes in the GnomAD database, including 104,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13042 hom., cov: 33)
  • Exomes 𝑓: 0.35 (91390 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00400
• Publications: 25 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=-0.83).
• BP6: Variant 9-113388911-A-G is Benign according to our data. Variant chr9-113388911-A-G is described in ClinVar as Benign. ClinVar VariationId is 1180338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.931+66T>C		intron_variant	Intron 11 of 11	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.931+66T>C		intron_variant	Intron 11 of 11	1	NM_000031.6	ENSP00000386284.3
ALAD	ENST00000482847.5	n.1204+66T>C		intron_variant	Intron 11 of 11	2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61322 AN: 151966 Hom.: 13022 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.346 AC: 504797 AN: 1459516 Hom.: 91390 AF XY: 0.347 AC XY: 252044 AN XY: 726100

African (AFR) AF: 0.502 AC: 16797 AN: 33446

American (AMR) AF: 0.645 AC: 28816 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7553 AN: 26120

East Asian (EAS) AF: 0.433 AC: 17177 AN: 39674

South Asian (SAS) AF: 0.418 AC: 35991 AN: 86164

European-Finnish (FIN) AF: 0.326 AC: 17119 AN: 52552

Middle Eastern (MID) AF: 0.409 AC: 2353 AN: 5760

European-Non Finnish (NFE) AF: 0.322 AC: 357147 AN: 1110760

Other (OTH) AF: 0.362 AC: 21844 AN: 60334

GnomAD4 genome AF: 0.404 AC: 61380 AN: 152084 Hom.: 13042 Cov.: 33 AF XY: 0.405 AC XY: 30102 AN XY: 74348

African (AFR) AF: 0.490 AC: 20347 AN: 41488

American (AMR) AF: 0.538 AC: 8224 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1029 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2231 AN: 5158

South Asian (SAS) AF: 0.419 AC: 2023 AN: 4828

European-Finnish (FIN) AF: 0.326 AC: 3443 AN: 10574

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22599 AN: 67962

Other (OTH) AF: 0.412 AC: 870 AN: 2112

Alfa AF: 0.358 Hom.: 46636

Bravo AF: 0.426

Asia WGS AF: 0.448 AC: 1554 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.83
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		0.0040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1805313; hg19: chr9-116151191; COSMIC: COSV52959100; COSMIC: COSV52959100;