9-113386978-C-T

Variant names:

• chr9-113386978-C-T
• rs11789221
• NM_000031.6:c.*1322G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000409155.8(ALAD):​c.*1322G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 152,410 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (0 hom.)
• Consequence: ALAD ENST00000409155.8 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.173
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-113386978-C-T is Benign according to our data. Variant chr9-113386978-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 914516.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00562 (856/152300) while in subpopulation NFE AF = 0.00838 (570/68030). AF 95% confidence interval is 0.00781. There are 7 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409155.8. 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.*1322G>A		3_prime_UTR	Exon 12 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.*1322G>A		3_prime_UTR	Exon 12 of 12	NP_001003945.1
	ALAD	NM_001317745.2		c.*1322G>A		3_prime_UTR	Exon 11 of 11	NP_001304674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.*1322G>A		3_prime_UTR	Exon 12 of 12	ENSP00000386284.3
	ALAD	ENST00000482847.5	TSL:2	n.2588G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 858 AN: 152182 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00839

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00909 AC: 1 AN: 110 Hom.: 0 Cov.: 0 AF XY: 0.0128 AC XY: 1 AN XY: 78

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0167 AC: 1 AN: 60

Other (OTH) AF: 0.00 AC: 0 AN: 14

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152300 Hom.: 7 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74462

African (AFR) AF: 0.00103 AC: 43 AN: 41548

American (AMR) AF: 0.00726 AC: 111 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00838 AC: 570 AN: 68030

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00684 Hom.: 1

Bravo AF: 0.00473

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.68
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs11789221; hg19: chr9-116149258;