chr12-102894798-T-A

Variant names:

• chr12-102894798-T-A
• NM_000277.3:c.289A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000277.3(PAH):​c.289A>T​(p.Ile97Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. I97L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3038612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.289A>T	p.Ile97Phe	missense_variant	Exon 3 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.289A>T	p.Ile97Phe	missense_variant	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2	c.289A>T	p.Ile97Phe	missense_variant	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.863-9900T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.289A>T	p.Ile97Phe	missense_variant	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	D;T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.49	N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.078	T;T;D;T
Sift4G	Benign	0.067	T;T;T;.
Polyphen		0.050	B;.;.;.
Vest4		0.59
MutPred		0.47		Gain of methylation at K96 (P = 0.0392);.;Gain of methylation at K96 (P = 0.0392);Gain of methylation at K96 (P = 0.0392);
MVP		0.92
MPC		0.053
ClinPred		0.44	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103288576;