chr12-102846935-G-C

Position:

• chr12-102846935-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000277.3(PAH):​c.929C>G​(p.Ser310Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S310Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 13) in uniprot entity PH4H_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 12-102846935-G-C is Pathogenic according to our data. Variant chr12-102846935-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2677442.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.929C>G	p.Ser310Cys	missense_variant	9/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.929C>G	p.Ser310Cys	missense_variant	10/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.929C>G	p.Ser310Cys	missense_variant	9/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461484 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.90		Loss of disorder (P = 0.0413);.;
MVP		0.99
MPC		0.24
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62642913; hg19: chr12-103240713;