chr12-102866605-T-G

Position:

• chr12-102866605-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000277.3(PAH):​c.500A>C​(p.Asn167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N167I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.267

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102866605-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.500A>C	p.Asn167Thr	missense_variant	5/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.500A>C	p.Asn167Thr	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2	c.500A>C	p.Asn167Thr	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1378T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.500A>C	p.Asn167Thr	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.596A>C		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.485A>C	p.Asn162Thr	missense_variant	6/14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10857A>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0082	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.11	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	B;.
Vest4		0.51
MutPred		0.67		Gain of phosphorylation at N167 (P = 0.0166);.;
MVP		0.81
MPC		0.037
ClinPred		0.85	D
GERP RS		-4.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.38
gMVP		0.82

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: rs77554925; hg19: chr12-103260383;