NM_000031.6:c.-76+2615G>T

Variant names:

• chr9-113398597-C-A
• rs818687
• NM_000031.6:c.-76+2615G>T

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+2615G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,166 control chromosomes in the GnomAD database, including 2,532 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 0.18 (2532 hom., cov: 32)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.-76+2615G>T		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+2615G>T		intron_variant	Intron 1 of 11	1	NM_000031.6	ENSP00000386284.3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26913 AN: 152048 Hom.: 2535 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0411

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.160

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

GnomAD4 genome AF: 0.177 AC: 26919 AN: 152166 Hom.: 2532 Cov.: 32 AF XY: 0.173 AC XY: 12897 AN XY: 74408

African (AFR) AF: 0.220 AC: 9130 AN: 41508

American (AMR) AF: 0.132 AC: 2019 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3472

East Asian (EAS) AF: 0.0416 AC: 216 AN: 5192

South Asian (SAS) AF: 0.105 AC: 506 AN: 4818

European-Finnish (FIN) AF: 0.160 AC: 1697 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12430 AN: 67982

Other (OTH) AF: 0.158 AC: 335 AN: 2114

Alfa AF: 0.178 Hom.: 1171

Bravo AF: 0.176

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.43
DANN	Benign	0.40
PhyloP100		-0.49
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: rs818687; hg19: chr9-116160877;