9-113396819-C-T

Variant names:

• chr9-113396819-C-T
• rs2792818
• NM_000031.6:c.-75-3185G>A

Variant summary

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

The NM_000031.6(ALAD):​c.-75-3185G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,982 control chromosomes in the GnomAD database, including 2,481 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 0.17 (2465 hom., cov: 31)
  • Exomes 𝑓: 0.18 (16 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.-75-3185G>A		intron	N/A	NP_000022.3
	ALAD	NM_001003945.3		c.-154-3185G>A		intron	N/A	NP_001003945.1
	ALAD	NM_001317745.2		c.-48-3185G>A		intron	N/A	NP_001304674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.-75-3185G>A		intron	N/A	ENSP00000386284.3
	ALAD	ENST00000445750.1	TSL:3	c.-605G>A		5_prime_UTR	Exon 1 of 2	ENSP00000398438.1
	ALAD	ENST00000448137.5	TSL:4	c.-49+1259G>A		intron	N/A	ENSP00000392748.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26467 AN: 151846 Hom.: 2453 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.178 AC: 181 AN: 1018 Hom.: 16 Cov.: 0 AF XY: 0.179 AC XY: 117 AN XY: 654

African (AFR) AF: 0.167 AC: 2 AN: 12

American (AMR) AF: 0.500 AC: 4 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 28

South Asian (SAS) AF: 0.167 AC: 4 AN: 24

European-Finnish (FIN) AF: 0.206 AC: 49 AN: 238

Middle Eastern (MID) AF: 0.222 AC: 4 AN: 18

European-Non Finnish (NFE) AF: 0.167 AC: 98 AN: 588

Other (OTH) AF: 0.200 AC: 20 AN: 100

GnomAD4 genome AF: 0.174 AC: 26507 AN: 151964 Hom.: 2465 Cov.: 31 AF XY: 0.174 AC XY: 12965 AN XY: 74298

African (AFR) AF: 0.192 AC: 7953 AN: 41418

American (AMR) AF: 0.115 AC: 1754 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 914 AN: 3462

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5158

South Asian (SAS) AF: 0.183 AC: 879 AN: 4816

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10576

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11890 AN: 67960

Other (OTH) AF: 0.164 AC: 346 AN: 2114

Alfa AF: 0.171 Hom.: 4280

Bravo AF: 0.165

Asia WGS AF: 0.117 AC: 410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.40
DANN	Benign	0.62
PhyloP100		-1.3
PromoterAI		-0.023	Neutral
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: rs2792818; hg19: chr9-116159099;