chr9-113387687-C-T

Variant names:

• chr9-113387687-C-T
• rs818707
• NM_000031.6:c.*613G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000031.6(ALAD):​c.*613G>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 0.0935 in 161,384 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (852 hom., cov: 32)
  • Exomes 𝑓: 0.098 (54 hom.)
• Consequence: ALAD NM_000031.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-113387687-C-T is Benign according to our data. Variant chr9-113387687-C-T is described in ClinVar as Benign. ClinVar VariationId is 364631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAD	NM_000031.6	c.*613G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000409155.8	NP_000022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAD	ENST00000409155.8	c.*613G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_000031.6	ENSP00000386284.3
ALAD	ENST00000482847.5	n.1879G>A		non_coding_transcript_exon_variant	Exon 12 of 12	2

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14191 AN: 152054 Hom.: 852 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.0889

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0979 AC: 902 AN: 9210 Hom.: 54 Cov.: 0 AF XY: 0.103 AC XY: 483 AN XY: 4706

African (AFR) AF: 0.0244 AC: 2 AN: 82

American (AMR) AF: 0.0717 AC: 146 AN: 2036

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 7 AN: 66

East Asian (EAS) AF: 0.0388 AC: 19 AN: 490

South Asian (SAS) AF: 0.179 AC: 191 AN: 1070

European-Finnish (FIN) AF: 0.0703 AC: 9 AN: 128

Middle Eastern (MID) AF: 0.125 AC: 1 AN: 8

European-Non Finnish (NFE) AF: 0.0996 AC: 492 AN: 4940

Other (OTH) AF: 0.0897 AC: 35 AN: 390

GnomAD4 genome AF: 0.0932 AC: 14186 AN: 152174 Hom.: 852 Cov.: 32 AF XY: 0.0930 AC XY: 6919 AN XY: 74390

African (AFR) AF: 0.0223 AC: 926 AN: 41566

American (AMR) AF: 0.0888 AC: 1356 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3466

East Asian (EAS) AF: 0.0578 AC: 299 AN: 5172

South Asian (SAS) AF: 0.176 AC: 846 AN: 4814

European-Finnish (FIN) AF: 0.110 AC: 1165 AN: 10580

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8499 AN: 67992

Other (OTH) AF: 0.103 AC: 218 AN: 2114

Alfa AF: 0.118 Hom.: 936

Bravo AF: 0.0894

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porphobilinogen synthase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs818707; hg19: chr9-116149967;