12-102866623-A-G

Position:

• chr12-102866623-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):​c.482T>C​(p.Phe161Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.20

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 12-102866623-A-G is Pathogenic according to our data. Variant chr12-102866623-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102866623-A-G is described in Lovd as [Pathogenic]. Variant chr12-102866623-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.482T>C	p.Phe161Ser	missense_variant	5/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.807+1396A>G		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.482T>C	p.Phe161Ser	missense_variant	6/14
PAH	XM_017019370.2	c.482T>C	p.Phe161Ser	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.482T>C	p.Phe161Ser	missense_variant	5/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.578T>C		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.467T>C	p.Phe156Ser	missense_variant	6/14	5
PAH	ENST00000551988.5	n.530+10839T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2018	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.91		Gain of disorder (P = 0.0017);.;
MVP		0.99
MPC		0.29
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.94
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs79635844; hg19: chr12-103260401;