9-113389085-C-G

Variant names:

• chr9-113389085-C-G
• rs121912981
• NM_000031.6:c.823G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000031.6(ALAD):​c.823G>C​(p.Val275Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V275M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALAD NM_000031.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

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.823G>C	p.Val275Leu	missense	Exon 11 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.910G>C	p.Val304Leu	missense	Exon 11 of 12	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.799G>C	p.Val267Leu	missense	Exon 10 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.823G>C	p.Val275Leu	missense	Exon 11 of 12	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907374.1		c.886G>C	p.Val296Leu	missense	Exon 11 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.880G>C	p.Val294Leu	missense	Exon 11 of 12	ENSP00000577418.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.76
Sift	Benign	0.052	T
Sift4G	Uncertain	0.023	D
Polyphen		0.37	B
Vest4		0.83
MutPred		0.75		Loss of phosphorylation at Y276 (P = 0.1297)
MVP		0.91
MPC		0.91
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.95
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121912981; hg19: chr9-116151365;