12-102846901-G-A

Variant names:

• chr12-102846901-G-A
• rs61747292
• NM_000277.3:c.963C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BS2 BS3_Supporting BS1 BP7

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 homozygotes in gnomAD. 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: (BS1, BP7, BS3_Supporting, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229873/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.014 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (54 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8 O:1
• Conservation: PhyloP100: -1.48
• Publications: 6 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 -10 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.963C>T	p.Leu321Leu	synonymous	Exon 9 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.963C>T	p.Leu321Leu	synonymous	Exon 10 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.963C>T	p.Leu321Leu	synonymous	Exon 9 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1062C>T	p.Leu354Leu	synonymous	Exon 10 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.963C>T	p.Leu321Leu	synonymous	Exon 9 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152092 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00385 AC: 968 AN: 251262 AF XY: 0.00305

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00156 AC: 2275 AN: 1461080 Hom.: 54 Cov.: 30 AF XY: 0.00134 AC XY: 973 AN XY: 726900

African (AFR) AF: 0.0561 AC: 1875 AN: 33416

American (AMR) AF: 0.00277 AC: 124 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111360

Other (OTH) AF: 0.00379 AC: 229 AN: 60354

GnomAD4 genome AF: 0.0144 AC: 2198 AN: 152210 Hom.: 69 Cov.: 32 AF XY: 0.0140 AC XY: 1040 AN XY: 74424

African (AFR) AF: 0.0503 AC: 2087 AN: 41514

American (AMR) AF: 0.00517 AC: 79 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68012

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00834 Hom.: 16

Bravo AF: 0.0167

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Phenylketonuria (4)
-	-	3	not specified (3)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.38
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61747292; hg19: chr12-103240679;