NM_000031.6:c.168T>C

Variant names:

• chr9-113391620-A-G
• rs1139488
• NM_000031.6:c.168T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000031.6(ALAD):​c.168T>C​(p.Tyr56Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,610,778 control chromosomes in the GnomAD database, including 108,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9990 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98426 hom.)
• Consequence: ALAD NM_000031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.120
• Publications: 27 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-113391620-A-G is Benign according to our data. Variant chr9-113391620-A-G is described in ClinVar as Benign. ClinVar VariationId is 364653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 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.168T>C	p.Tyr56Tyr	synonymous	Exon 4 of 12	NP_000022.3
	ALAD	NM_001003945.3		c.255T>C	p.Tyr85Tyr	synonymous	Exon 4 of 12	NP_001003945.1
	ALAD	NM_001317745.2		c.144T>C	p.Tyr48Tyr	synonymous	Exon 3 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.168T>C	p.Tyr56Tyr	synonymous	Exon 4 of 12	ENSP00000386284.3
	ALAD	ENST00000907374.1		c.231T>C	p.Tyr77Tyr	synonymous	Exon 4 of 12	ENSP00000577433.1
	ALAD	ENST00000907359.1		c.168T>C	p.Tyr56Tyr	synonymous	Exon 4 of 12	ENSP00000577418.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54313 AN: 151930 Hom.: 9974 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.347 AC: 86937 AN: 250642 AF XY: 0.342

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.454

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.363 AC: 530214 AN: 1458730 Hom.: 98426 Cov.: 34 AF XY: 0.360 AC XY: 261336 AN XY: 725804

African (AFR) AF: 0.320 AC: 10690 AN: 33430

American (AMR) AF: 0.300 AC: 13424 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5537 AN: 26120

East Asian (EAS) AF: 0.426 AC: 16885 AN: 39676

South Asian (SAS) AF: 0.258 AC: 22252 AN: 86208

European-Finnish (FIN) AF: 0.424 AC: 22597 AN: 53278

Middle Eastern (MID) AF: 0.239 AC: 1380 AN: 5762

European-Non Finnish (NFE) AF: 0.375 AC: 416524 AN: 1109282

Other (OTH) AF: 0.347 AC: 20925 AN: 60292

GnomAD4 genome AF: 0.358 AC: 54361 AN: 152048 Hom.: 9990 Cov.: 32 AF XY: 0.357 AC XY: 26558 AN XY: 74310

African (AFR) AF: 0.322 AC: 13356 AN: 41454

American (AMR) AF: 0.346 AC: 5289 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2394 AN: 5150

South Asian (SAS) AF: 0.261 AC: 1257 AN: 4822

European-Finnish (FIN) AF: 0.427 AC: 4511 AN: 10570

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25735 AN: 67974

Other (OTH) AF: 0.337 AC: 712 AN: 2112

Alfa AF: 0.359 Hom.: 13061

Bravo AF: 0.348

Asia WGS AF: 0.344 AC: 1195 AN: 3478

EpiCase AF: 0.348

EpiControl AF: 0.351

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Porphobilinogen synthase deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.2
DANN	Benign	0.49
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs1139488; hg19: chr9-116153900; COSMIC: COSV52957876; COSMIC: COSV52957876;