rs8177796

Variant names:

• chr9-113393148-G-A
• rs8177796
• NM_000031.6:c.113+299C>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.113+299C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0739 in 425,936 control chromosomes in the GnomAD database, including 1,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (522 hom., cov: 31)
  • Exomes 𝑓: 0.071 (862 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93
• Publications: 4 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 9-113393148-G-A is Benign according to our data. Variant chr9-113393148-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.113+299C>T		intron_variant	Intron 2 of 11	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.113+299C>T		intron_variant	Intron 2 of 11	1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes AF: 0.0800 AC: 12159 AN: 152078 Hom.: 523 Cov.: 31

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.0574

GnomAD4 exome AF: 0.0705 AC: 19310 AN: 273740 Hom.: 862 Cov.: 0 AF XY: 0.0666 AC XY: 9716 AN XY: 145972

African (AFR) AF: 0.0899 AC: 733 AN: 8158

American (AMR) AF: 0.0376 AC: 498 AN: 13242

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 534 AN: 7824

East Asian (EAS) AF: 0.00 AC: 0 AN: 15374

South Asian (SAS) AF: 0.0311 AC: 1256 AN: 40434

European-Finnish (FIN) AF: 0.134 AC: 1816 AN: 13596

Middle Eastern (MID) AF: 0.0621 AC: 70 AN: 1128

European-Non Finnish (NFE) AF: 0.0836 AC: 13290 AN: 158884

Other (OTH) AF: 0.0737 AC: 1113 AN: 15100

GnomAD4 genome AF: 0.0799 AC: 12167 AN: 152196 Hom.: 522 Cov.: 31 AF XY: 0.0802 AC XY: 5971 AN XY: 74416

African (AFR) AF: 0.0931 AC: 3865 AN: 41508

American (AMR) AF: 0.0396 AC: 606 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0294 AC: 142 AN: 4826

European-Finnish (FIN) AF: 0.131 AC: 1385 AN: 10590

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0847 AC: 5759 AN: 68008

Other (OTH) AF: 0.0568 AC: 120 AN: 2112

Alfa AF: 0.0775 Hom.: 677

Bravo AF: 0.0728

Asia WGS AF: 0.0160 AC: 55 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

- -

Jun 18, 2021

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	12
DANN	Benign	0.52
PhyloP100		1.9
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: rs8177796; hg19: chr9-116155428;