chr9-113389247-G-A

Variant names:

• chr9-113389247-G-A
• rs8177812
• NM_000031.6:c.802-141C>T

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.802-141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,405,648 control chromosomes in the GnomAD database, including 15,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1732 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13360 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600
• Publications: 11 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=-0.87).
• BP6: Variant 9-113389247-G-A is Benign according to our data. Variant chr9-113389247-G-A is described in ClinVar as Benign. ClinVar VariationId is 1267385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.802-141C>T		intron_variant	Intron 10 of 11	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.802-141C>T		intron_variant	Intron 10 of 11	1	NM_000031.6	ENSP00000386284.3
ALAD	ENST00000482847.5	n.1075-141C>T		intron_variant	Intron 10 of 11	2

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21438 AN: 152044 Hom.: 1733 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.138 AC: 173262 AN: 1253486 Hom.: 13360 AF XY: 0.142 AC XY: 88527 AN XY: 623392

African (AFR) AF: 0.125 AC: 3579 AN: 28726

American (AMR) AF: 0.234 AC: 8264 AN: 35256

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2531 AN: 23300

East Asian (EAS) AF: 0.204 AC: 7189 AN: 35154

South Asian (SAS) AF: 0.266 AC: 19854 AN: 74600

European-Finnish (FIN) AF: 0.115 AC: 5472 AN: 47590

Middle Eastern (MID) AF: 0.141 AC: 572 AN: 4070

European-Non Finnish (NFE) AF: 0.124 AC: 118057 AN: 951886

Other (OTH) AF: 0.146 AC: 7744 AN: 52904

GnomAD4 genome AF: 0.141 AC: 21439 AN: 152162 Hom.: 1732 Cov.: 32 AF XY: 0.143 AC XY: 10665 AN XY: 74388

African (AFR) AF: 0.124 AC: 5137 AN: 41512

American (AMR) AF: 0.195 AC: 2988 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3472

East Asian (EAS) AF: 0.229 AC: 1181 AN: 5166

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4818

European-Finnish (FIN) AF: 0.113 AC: 1194 AN: 10604

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8627 AN: 67990

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.136 Hom.: 4744

Bravo AF: 0.144

Asia WGS AF: 0.233 AC: 809 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	-0.87
CADD	Benign	0.86
DANN	Benign	0.72
PhyloP100		0.0060
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: rs8177812; hg19: chr9-116151527; COSMIC: COSV52961248; COSMIC: COSV52961248;