chr9-113386487-CTT-C

Position:

• chr9-113386487-CTT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000031.6(ALAD):​c.*1811_*1812del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 152,180 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ALAD NM_000031.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.446

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 9-113386487-CTT-C is Benign according to our data. Variant chr9-113386487-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 364621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1934/152180) while in subpopulation AFR AF= 0.0414 (1717/41514). AF 95% confidence interval is 0.0397. There are 35 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.*1811_*1812del		3_prime_UTR_variant	12/12	ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.*1811_*1812del		3_prime_UTR_variant	12/12	1	NM_000031.6	P1
ALAD	ENST00000482847.5	n.3077_3078del		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152064 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0120

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

GnomAD4 genome AF: 0.0127 AC: 1934 AN: 152180 Hom.: 35 Cov.: 32 AF XY: 0.0124 AC XY: 924 AN XY: 74404

Gnomad4 AFR AF: 0.0414

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0110 Hom.: 2

Bravo AF: 0.0149

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Porphobilinogen synthase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs142213018; hg19: chr9-116148767;