rs1800435

chr9-113391611-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000031.6(ALAD):c.177G>C(p.Lys59Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,613,738 control chromosomes in the GnomAD database, including 6,502 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (416 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6086 hom.)
• Consequence: ALAD NM_000031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 2.03

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013033152).
• BP6: Variant 9-113391611-C-G is Benign according to our data. Variant chr9-113391611-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 16864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-113391611-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAD	NM_000031.6	c.177G>C	p.Lys59Asn	missense_variant	4/12	ENST00000409155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAD	ENST00000409155.8	c.177G>C	p.Lys59Asn	missense_variant	4/12	1	NM_000031.6	P1

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9536 AN: 152168 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.0419

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.0703

GnomAD3 exomes AF: 0.0827 AC: 20774 AN: 251162 Hom.: 1166 AF XY: 0.0896 AC XY: 12168 AN XY: 135792

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0362

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.0776

Gnomad NFE exome AF: 0.0842

Gnomad OTH exome AF: 0.0942

GnomAD4 exome AF: 0.0855 AC: 124884 AN: 1461452 Hom.: 6086 Cov.: 32 AF XY: 0.0878 AC XY: 63842 AN XY: 727058

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.0427

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.0578

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0826

Gnomad4 OTH exome AF: 0.0907

GnomAD4 genome AF: 0.0626 AC: 9532 AN: 152286 Hom.: 416 Cov.: 32 AF XY: 0.0633 AC XY: 4716 AN XY: 74466

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0535

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.0420

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0719

Gnomad4 NFE AF: 0.0798

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0885 Hom.: 598

Bravo AF: 0.0581

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.0834 AC: 717

ExAC AF: 0.0825 AC: 10021

Asia WGS AF: 0.0840 AC: 293 AN: 3478

EpiCase AF: 0.0876

EpiControl AF: 0.0896

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porphobilinogen synthase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 25239657, 16909025, 9593628, 11342419, 11071662) -

AMINOLEVULINATE DEHYDRATASE, ALAD*1/ALAD*2 POLYMORPHISM Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1991

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	17
Dann	Benign	0.27
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.6	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	4.9	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.038
MutPred		0.17		Loss of methylation at K59 (P = 0.0155);.;
MPC		0.44
ClinPred		0.0039	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.50

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: rs1800435; hg19: chr9-116153891; COSMIC: COSV52957749; COSMIC: COSV52957749;