rs1042503

Variant names:

• chr12-102852922-C-T
• rs1042503
• NM_000277.3:c.735G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-102852922-C-T
• chr12-102852922-C-A
• chr12-102852922-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145982/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.21 (4861 hom., cov: 32)
  • Exomes 𝑓: 0.26 (56669 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:16 O:1
• Conservation: PhyloP100: -0.253
• Publications: 47 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 -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.735G>A	p.Val245Val	synonymous	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.735G>A	p.Val245Val	synonymous	Exon 8 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.735G>A	p.Val245Val	synonymous	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.735G>A	p.Val245Val	synonymous	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.735G>A	p.Val245Val	synonymous	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32231 AN: 151912 Hom.: 4861 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.291 AC: 72975 AN: 251140 AF XY: 0.297

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.753

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.260 AC: 379698 AN: 1461694 Hom.: 56669 Cov.: 35 AF XY: 0.264 AC XY: 192222 AN XY: 727156

African (AFR) AF: 0.0385 AC: 1290 AN: 33478

American (AMR) AF: 0.205 AC: 9186 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7551 AN: 26136

East Asian (EAS) AF: 0.759 AC: 30118 AN: 39694

South Asian (SAS) AF: 0.369 AC: 31813 AN: 86254

European-Finnish (FIN) AF: 0.308 AC: 16437 AN: 53414

Middle Eastern (MID) AF: 0.303 AC: 1746 AN: 5768

European-Non Finnish (NFE) AF: 0.238 AC: 265096 AN: 1111846

Other (OTH) AF: 0.273 AC: 16461 AN: 60386

GnomAD4 genome AF: 0.212 AC: 32232 AN: 152030 Hom.: 4861 Cov.: 32 AF XY: 0.218 AC XY: 16165 AN XY: 74304

African (AFR) AF: 0.0493 AC: 2044 AN: 41488

American (AMR) AF: 0.194 AC: 2969 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3468

East Asian (EAS) AF: 0.750 AC: 3859 AN: 5144

South Asian (SAS) AF: 0.372 AC: 1786 AN: 4800

European-Finnish (FIN) AF: 0.296 AC: 3129 AN: 10564

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16635 AN: 67970

Other (OTH) AF: 0.232 AC: 490 AN: 2112

Alfa AF: 0.228 Hom.: 7014

Bravo AF: 0.198

Asia WGS AF: 0.465 AC: 1616 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.248

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	Phenylketonuria (9)
-	-	4	not specified (4)
-	-	3	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		-0.25
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1042503; hg19: chr12-103246700; COSMIC: COSV61020278; COSMIC: COSV61020278;