rs2228083

Variant names:

• chr9-113390660-G-A
• rs2228083
• NM_000031.6:c.414C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000031.6(ALAD):​c.414C>T​(p.Asn138Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 1,613,900 control chromosomes in the GnomAD database, including 5,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (559 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4938 hom.)
• Consequence: ALAD NM_000031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.590
• Publications: 16 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-113390660-G-A is Benign according to our data. Variant chr9-113390660-G-A is described in ClinVar as Benign. ClinVar VariationId is 364650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.414C>T	p.Asn138Asn	synonymous	Exon 6 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.501C>T	p.Asn167Asn	synonymous	Exon 6 of 12	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.390C>T	p.Asn130Asn	synonymous	Exon 5 of 11	NP_001304674.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.414C>T	p.Asn138Asn	synonymous	Exon 6 of 12	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907374.1		c.477C>T	p.Asn159Asn	synonymous	Exon 6 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.471C>T	p.Asn157Asn	synonymous	Exon 6 of 12	ENSP00000577418.1

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 12358 AN: 152186 Hom.: 558 Cov.: 33

Gnomad AFR AF: 0.0872

Gnomad AMI AF: 0.0727

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.0931

Gnomad SAS AF: 0.0682

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0838

Gnomad OTH AF: 0.0822

GnomAD2 exomes AF: 0.0746 AC: 18643 AN: 249910 AF XY: 0.0747

Gnomad AFR exome AF: 0.0862

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0935

Gnomad FIN exome AF: 0.0916

Gnomad NFE exome AF: 0.0823

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0798 AC: 116664 AN: 1461596 Hom.: 4938 Cov.: 34 AF XY: 0.0795 AC XY: 57789 AN XY: 727084

African (AFR) AF: 0.0850 AC: 2846 AN: 33474

American (AMR) AF: 0.0426 AC: 1905 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 824 AN: 26126

East Asian (EAS) AF: 0.0652 AC: 2589 AN: 39686

South Asian (SAS) AF: 0.0691 AC: 5956 AN: 86242

European-Finnish (FIN) AF: 0.0902 AC: 4815 AN: 53370

Middle Eastern (MID) AF: 0.0376 AC: 217 AN: 5768

European-Non Finnish (NFE) AF: 0.0835 AC: 92802 AN: 1111864

Other (OTH) AF: 0.0780 AC: 4710 AN: 60378

GnomAD4 genome AF: 0.0812 AC: 12372 AN: 152304 Hom.: 559 Cov.: 33 AF XY: 0.0801 AC XY: 5965 AN XY: 74472

African (AFR) AF: 0.0872 AC: 3627 AN: 41576

American (AMR) AF: 0.0608 AC: 930 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.0937 AC: 484 AN: 5164

South Asian (SAS) AF: 0.0683 AC: 330 AN: 4832

European-Finnish (FIN) AF: 0.0879 AC: 933 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0838 AC: 5699 AN: 68024

Other (OTH) AF: 0.0823 AC: 174 AN: 2114

Alfa AF: 0.0793 Hom.: 789

Bravo AF: 0.0775

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0761

EpiControl AF: 0.0695

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Porphobilinogen synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2228083; hg19: chr9-116152940; COSMIC: COSV107318289; COSMIC: COSV107318289;