NM_000277.3:c.*187G>A

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), G2P, ClinGen, Myriad Women’s Health
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.*187G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.*187G>A		3_prime_UTR_variant	Exon 14 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.*187G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_000277.3	ENSP00000448059.1

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Phenylketonuria Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;