NM_000031.6:c.262-37T>C

Variant names:

• chr9-113390970-A-G
• rs1805316
• NM_000031.6:c.262-37T>C

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.262-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,612,644 control chromosomes in the GnomAD database, including 5,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.082 (550 hom., cov: 33)
  • Exomes 𝑓: 0.081 (5320 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.83
• Publications: 5 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-113390970-A-G is Benign according to our data. Variant chr9-113390970-A-G is described in ClinVar as Benign. ClinVar VariationId is 1227501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.262-37T>C		intron	N/A	NP_000022.3
	ALAD	NM_001003945.3		c.349-37T>C		intron	N/A	NP_001003945.1
	ALAD	NM_001317745.2		c.238-37T>C		intron	N/A	NP_001304674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.262-37T>C		intron	N/A	ENSP00000386284.3
	ALAD	ENST00000448137.5	TSL:4	c.289-37T>C		intron	N/A	ENSP00000392748.1
	ALAD	ENST00000464749.5	TSL:4	n.258-37T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12450 AN: 152144 Hom.: 550 Cov.: 33

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0873

Gnomad OTH AF: 0.0587

GnomAD2 exomes AF: 0.0700 AC: 17481 AN: 249572 AF XY: 0.0703

Gnomad AFR exome AF: 0.0971

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0880

Gnomad OTH exome AF: 0.0642

GnomAD4 exome AF: 0.0815 AC: 118999 AN: 1460382 Hom.: 5320 Cov.: 34 AF XY: 0.0801 AC XY: 58155 AN XY: 726378

African (AFR) AF: 0.0939 AC: 3140 AN: 33454

American (AMR) AF: 0.0325 AC: 1452 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1687 AN: 26112

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39680

South Asian (SAS) AF: 0.0342 AC: 2946 AN: 86204

European-Finnish (FIN) AF: 0.133 AC: 7048 AN: 52980

Middle Eastern (MID) AF: 0.0628 AC: 352 AN: 5608

European-Non Finnish (NFE) AF: 0.0881 AC: 97855 AN: 1111306

Other (OTH) AF: 0.0748 AC: 4515 AN: 60338

GnomAD4 genome AF: 0.0818 AC: 12457 AN: 152262 Hom.: 550 Cov.: 33 AF XY: 0.0818 AC XY: 6092 AN XY: 74448

African (AFR) AF: 0.0949 AC: 3942 AN: 41548

American (AMR) AF: 0.0399 AC: 610 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4828

European-Finnish (FIN) AF: 0.132 AC: 1401 AN: 10610

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0873 AC: 5938 AN: 68014

Other (OTH) AF: 0.0581 AC: 123 AN: 2116

Alfa AF: 0.0849 Hom.: 321

Bravo AF: 0.0749

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.79
PhyloP100		2.8
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1805316; hg19: chr9-116153250;