rs142516271

Positions:

• chr12-102894798-T-C
• chr12-102894798-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000277.3(PAH):​c.289A>G​(p.Ile97Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2481207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.289A>G	p.Ile97Val	missense_variant	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.863-9900T>C		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.289A>G	p.Ile97Val	missense_variant	4/14		NP_001341233.1
PAH	XM_017019370.2	c.289A>G	p.Ile97Val	missense_variant	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.289A>G	p.Ile97Val	missense_variant	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251446 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.040	N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.29	T;T;T;.
Polyphen		0.0020	B;.;.;.
Vest4		0.46
MutPred		0.47		Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.88
MPC		0.028
ClinPred		0.21	T
GERP RS		6.2
Varity_R		0.24
gMVP		0.48

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: rs142516271; hg19: chr12-103288576;