rs1805312

Variant names:

• chr9-113390710-C-G
• rs1805312
• NM_000031.6:c.398-34G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-113390710-C-G
• chr9-113390710-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000031.6(ALAD):​c.398-34G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.085 in 1,607,220 control chromosomes in the GnomAD database, including 7,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (810 hom., cov: 33)
  • Exomes 𝑓: 0.086 (7139 hom.)
• Consequence: ALAD NM_000031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27
• 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-113390710-C-G is Benign according to our data. Variant chr9-113390710-C-G is described in ClinVar as Benign. ClinVar VariationId is 1178261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.205 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	NM_000031.6	MANE Select	c.398-34G>C		intron	N/A	NP_000022.3
	ALAD	NM_001003945.3		c.485-34G>C		intron	N/A	NP_001003945.1	P13716-2
	ALAD	NM_001317745.2		c.374-34G>C		intron	N/A	NP_001304674.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAD	ENST00000409155.8	TSL:1 MANE Select	c.398-34G>C		intron	N/A	ENSP00000386284.3	P13716-1
	ALAD	ENST00000907359.1		c.421G>C	p.Gly141Arg	missense	Exon 6 of 12	ENSP00000577418.1
	ALAD	ENST00000907390.1		c.421G>C	p.Gly141Arg	missense	Exon 6 of 12	ENSP00000577449.1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11965 AN: 152140 Hom.: 801 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0923

GnomAD2 exomes AF: 0.114 AC: 26537 AN: 233556 AF XY: 0.105

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.0537

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0775

Gnomad NFE exome AF: 0.0797

Gnomad OTH exome AF: 0.0954

GnomAD4 exome AF: 0.0856 AC: 124614 AN: 1454962 Hom.: 7139 Cov.: 35 AF XY: 0.0848 AC XY: 61355 AN XY: 723378

African (AFR) AF: 0.0136 AC: 455 AN: 33376

American (AMR) AF: 0.317 AC: 13628 AN: 43044

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 1420 AN: 25974

East Asian (EAS) AF: 0.160 AC: 6312 AN: 39368

South Asian (SAS) AF: 0.0739 AC: 6310 AN: 85410

European-Finnish (FIN) AF: 0.0773 AC: 4091 AN: 52916

Middle Eastern (MID) AF: 0.0439 AC: 253 AN: 5760

European-Non Finnish (NFE) AF: 0.0785 AC: 87086 AN: 1108970

Other (OTH) AF: 0.0841 AC: 5059 AN: 60144

GnomAD4 genome AF: 0.0787 AC: 11986 AN: 152258 Hom.: 810 Cov.: 33 AF XY: 0.0815 AC XY: 6065 AN XY: 74448

African (AFR) AF: 0.0198 AC: 824 AN: 41562

American (AMR) AF: 0.211 AC: 3220 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.151 AC: 780 AN: 5170

South Asian (SAS) AF: 0.0677 AC: 327 AN: 4828

European-Finnish (FIN) AF: 0.0766 AC: 813 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5563 AN: 68014

Other (OTH) AF: 0.0933 AC: 197 AN: 2112

Alfa AF: 0.0779 Hom.: 127

Bravo AF: 0.0904

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

ClinVar submissions

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	-0.90
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1805312; hg19: chr9-116152990;