NM_000277.3:c.1155C>G

Variant names:

• chr12-102843690-G-C
• rs772897
• NM_000277.3:c.1155C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP7

This summary comes from the ClinGen Evidence Repository: This c.1155C>G (p.Leu385=) synonymous variant in PAH is not predicted to have a splice-altering consequence. This variant was present at a high frequency of 0.840256 in 1000 genomes and 0.858145 in ExAC. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180265/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.84 (53986 hom., cov: 29)
  • Exomes 𝑓: 0.85 (528935 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.0970
• Publications: 34 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 -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.842 AC: 127910 AN: 151868 Hom.: 53951 Cov.: 29

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.846

Gnomad OTH AF: 0.844

GnomAD2 exomes AF: 0.861 AC: 216427 AN: 251268 AF XY: 0.860

Gnomad AFR exome AF: 0.799

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.822

Gnomad EAS exome AF: 0.839

Gnomad FIN exome AF: 0.907

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.851 AC: 1242694 AN: 1461134 Hom.: 528935 Cov.: 43 AF XY: 0.852 AC XY: 619004 AN XY: 726890

African (AFR) AF: 0.802 AC: 26836 AN: 33450

American (AMR) AF: 0.908 AC: 40567 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 21502 AN: 26130

East Asian (EAS) AF: 0.846 AC: 33568 AN: 39696

South Asian (SAS) AF: 0.889 AC: 76662 AN: 86246

European-Finnish (FIN) AF: 0.910 AC: 48602 AN: 53406

Middle Eastern (MID) AF: 0.857 AC: 4937 AN: 5762

European-Non Finnish (NFE) AF: 0.845 AC: 938782 AN: 1111384

Other (OTH) AF: 0.849 AC: 51238 AN: 60362

GnomAD4 genome AF: 0.842 AC: 128004 AN: 151986 Hom.: 53986 Cov.: 29 AF XY: 0.847 AC XY: 62900 AN XY: 74296

African (AFR) AF: 0.804 AC: 33295 AN: 41430

American (AMR) AF: 0.885 AC: 13510 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2846 AN: 3472

East Asian (EAS) AF: 0.840 AC: 4325 AN: 5148

South Asian (SAS) AF: 0.872 AC: 4187 AN: 4802

European-Finnish (FIN) AF: 0.907 AC: 9597 AN: 10586

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.846 AC: 57487 AN: 67966

Other (OTH) AF: 0.845 AC: 1787 AN: 2114

Alfa AF: 0.839 Hom.: 13908

Bravo AF: 0.837

EpiCase AF: 0.834

EpiControl AF: 0.837

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2022

ClinGen PAH Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

This c.1155C>G (p.Leu385=) synonymous variant in PAH is not predicted to have a splice-altering consequence. This variant was present at a high frequency of 0.840256 in 1000 genomes and 0.858145 in ExAC. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. -

Nov 16, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 16, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.2
DANN	Benign	0.60
PhyloP100		-0.097
Mutation Taster		=99/1	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: rs772897; hg19: chr12-103237468; COSMIC: COSV108133564;