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12-102838988-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000277.3(PAH):c.*187G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 617,870 control chromosomes in the GnomAD database, including 21,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 9832 hom., cov: 33)
Exomes 𝑓: 0.20 ( 11802 hom. )

Consequence

PAH
NM_000277.3 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.611
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 12-102838988-C-T is Benign according to our data. Variant chr12-102838988-C-T is described in ClinVar as [Benign]. Clinvar id is 306911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAHNM_000277.3 linkuse as main transcriptc.*187G>A 3_prime_UTR_variant 13/13 ENST00000553106.6
PAHNM_001354304.2 linkuse as main transcriptc.*187G>A 3_prime_UTR_variant 14/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.*187G>A 3_prime_UTR_variant 13/131 NM_000277.3 P1
PAHENST00000307000.7 linkuse as main transcriptc.*187G>A 3_prime_UTR_variant 14/145

Frequencies

GnomAD3 genomes
AF:
0.311
AC:
47242
AN:
152030
Hom.:
9798
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.581
Gnomad AMI
AF:
0.0888
Gnomad AMR
AF:
0.358
Gnomad ASJ
AF:
0.206
Gnomad EAS
AF:
0.00653
Gnomad SAS
AF:
0.167
Gnomad FIN
AF:
0.177
Gnomad MID
AF:
0.180
Gnomad NFE
AF:
0.200
Gnomad OTH
AF:
0.273
GnomAD4 exome
AF:
0.202
AC:
94267
AN:
465722
Hom.:
11802
Cov.:
4
AF XY:
0.198
AC XY:
49060
AN XY:
247452
show subpopulations
Gnomad4 AFR exome
AF:
0.579
Gnomad4 AMR exome
AF:
0.381
Gnomad4 ASJ exome
AF:
0.198
Gnomad4 EAS exome
AF:
0.00292
Gnomad4 SAS exome
AF:
0.178
Gnomad4 FIN exome
AF:
0.188
Gnomad4 NFE exome
AF:
0.197
Gnomad4 OTH exome
AF:
0.221
GnomAD4 genome
AF:
0.311
AC:
47330
AN:
152148
Hom.:
9832
Cov.:
33
AF XY:
0.305
AC XY:
22719
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.582
Gnomad4 AMR
AF:
0.358
Gnomad4 ASJ
AF:
0.206
Gnomad4 EAS
AF:
0.00655
Gnomad4 SAS
AF:
0.166
Gnomad4 FIN
AF:
0.177
Gnomad4 NFE
AF:
0.200
Gnomad4 OTH
AF:
0.270
Alfa
AF:
0.225
Hom.:
6056
Bravo
AF:
0.338
Asia WGS
AF:
0.121
AC:
420
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Phenylketonuria Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxSep 22, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
Cadd
Benign
6.8
Dann
Benign
0.29

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1801153; hg19: chr12-103232766; API