rs376480977

Variant names:

• chr12-102843771-T-A
• rs376480977
• NM_000277.3:c.1074A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102843771-T-A
• chr12-102843771-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PP4 PM3 PM2

This summary comes from the ClinGen Evidence Repository: The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID:23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID:23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID:24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748747/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: -0.0780
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1074A>T	p.Leu358Phe	missense	Exon 11 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1074A>T	p.Leu358Phe	missense	Exon 12 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.1074A>T	p.Leu358Phe	missense	Exon 11 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1173A>T	p.Leu391Phe	missense	Exon 12 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1152A>T	p.Leu384Phe	missense	Exon 11 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251142 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461536 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111830

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	1	-	Phenylketonuria (6)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	0.15
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		-0.078
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.71		Loss of catalytic residue at L358 (P = 0.0296)
MVP		0.98
MPC		0.25
ClinPred		0.99	D
GERP RS		0.33
Varity_R		0.88
gMVP		0.93
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs376480977; hg19: chr12-103237549;