NM_000277.3:c.1278T>C

Variant names:

• chr12-102840437-A-G
• rs59326968
• NM_000277.3:c.1278T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.16641; BP4: no impact on gene in SIFT, Polyphen2, MutationTaster. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145978/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.041 (467 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (389 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10 O:1
• Conservation: PhyloP100: 0.0610
• Publications: 5 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1278T>C	p.Asn426Asn	synonymous	Exon 12 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1278T>C	p.Asn426Asn	synonymous	Exon 13 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.1278T>C	p.Asn426Asn	synonymous	Exon 12 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1377T>C	p.Asn459Asn	synonymous	Exon 13 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1356T>C	p.Asn452Asn	synonymous	Exon 12 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6175 AN: 152134 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0110 AC: 2772 AN: 251446 AF XY: 0.00780

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00444 AC: 6484 AN: 1461546 Hom.: 389 Cov.: 31 AF XY: 0.00384 AC XY: 2791 AN XY: 727098

African (AFR) AF: 0.148 AC: 4950 AN: 33456

American (AMR) AF: 0.00883 AC: 395 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53404

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5766

European-Non Finnish (NFE) AF: 0.000427 AC: 475 AN: 1111732

Other (OTH) AF: 0.00921 AC: 556 AN: 60386

GnomAD4 genome AF: 0.0408 AC: 6205 AN: 152252 Hom.: 467 Cov.: 32 AF XY: 0.0391 AC XY: 2908 AN XY: 74432

African (AFR) AF: 0.142 AC: 5878 AN: 41534

American (AMR) AF: 0.0143 AC: 218 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68016

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0219 Hom.: 151

Bravo AF: 0.0470

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Phenylketonuria (4)
-	-	3	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.0
DANN	Benign	0.59
PhyloP100		0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs59326968; hg19: chr12-103234215;