NM_000031.6:c.-76+1425G>C

Variant names:

• chr9-113399787-C-G
• rs818688
• NM_000031.6:c.-76+1425G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000031.6(ALAD):​c.-76+1425G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 151,744 control chromosomes in the GnomAD database, including 14,572 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14572 hom., cov: 31)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.-76+1425G>C		intron_variant	Intron 1 of 11	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.-76+1425G>C		intron_variant	Intron 1 of 11	1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64763 AN: 151626 Hom.: 14535 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.400

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.427 AC: 64843 AN: 151744 Hom.: 14572 Cov.: 31 AF XY: 0.425 AC XY: 31475 AN XY: 74124

African (AFR) AF: 0.582 AC: 24073 AN: 41346

American (AMR) AF: 0.362 AC: 5525 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1350 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1234 AN: 5134

South Asian (SAS) AF: 0.436 AC: 2096 AN: 4808

European-Finnish (FIN) AF: 0.399 AC: 4196 AN: 10522

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25208 AN: 67906

Other (OTH) AF: 0.394 AC: 830 AN: 2104

Alfa AF: 0.413 Hom.: 1642

Bravo AF: 0.432

Asia WGS AF: 0.336 AC: 1167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.42
PhyloP100		-0.82
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs818688; hg19: chr9-116162067;