rs1801153

Variant names:

• chr12-102838988-C-T
• rs1801153
• NM_000277.3:c.*187G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000277.3(PAH):​c.*187G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 617,870 control chromosomes in the GnomAD database, including 21,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9832 hom., cov: 33)
  • Exomes 𝑓: 0.20 (11802 hom.)
• Consequence: PAH NM_000277.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.611
• Publications: 9 publications found

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-102838988-C-T is Benign according to our data. Variant chr12-102838988-C-T is described in ClinVar as Benign. ClinVar VariationId is 306911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. 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
	PAH	NM_000277.3	MANE Select	c.*187G>A		3_prime_UTR	Exon 13 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.*187G>A		3_prime_UTR	Exon 14 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.*187G>A		3_prime_UTR	Exon 13 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.*187G>A		3_prime_UTR	Exon 14 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.*187G>A		3_prime_UTR	Exon 13 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47242 AN: 152030 Hom.: 9798 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.00653

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.202 AC: 94267 AN: 465722 Hom.: 11802 Cov.: 4 AF XY: 0.198 AC XY: 49060 AN XY: 247452

African (AFR) AF: 0.579 AC: 7421 AN: 12818

American (AMR) AF: 0.381 AC: 8368 AN: 21956

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 2916 AN: 14726

East Asian (EAS) AF: 0.00292 AC: 91 AN: 31168

South Asian (SAS) AF: 0.178 AC: 8272 AN: 46358

European-Finnish (FIN) AF: 0.188 AC: 5676 AN: 30214

Middle Eastern (MID) AF: 0.195 AC: 463 AN: 2372

European-Non Finnish (NFE) AF: 0.197 AC: 55173 AN: 279452

Other (OTH) AF: 0.221 AC: 5887 AN: 26658

GnomAD4 genome AF: 0.311 AC: 47330 AN: 152148 Hom.: 9832 Cov.: 33 AF XY: 0.305 AC XY: 22719 AN XY: 74390

African (AFR) AF: 0.582 AC: 24124 AN: 41482

American (AMR) AF: 0.358 AC: 5469 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3468

East Asian (EAS) AF: 0.00655 AC: 34 AN: 5192

South Asian (SAS) AF: 0.166 AC: 801 AN: 4824

European-Finnish (FIN) AF: 0.177 AC: 1881 AN: 10600

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13601 AN: 67992

Other (OTH) AF: 0.270 AC: 571 AN: 2112

Alfa AF: 0.229 Hom.: 7506

Bravo AF: 0.338

Asia WGS AF: 0.121 AC: 420 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.29
PhyloP100		0.61
Mutation Taster		=100/0	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: rs1801153; hg19: chr12-103232766;