rs149538764

Variant names:

• chr12-102866681-C-T
• rs149538764
• NM_000277.3:c.442-18G>A

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP7

This summary comes from the ClinGen Evidence Repository: The c.442-18G>A variant in PAH has not been reported in the literature to our knowledge. This variant has a MAF of 0.00067 in the gnomAD Latino population. This is too high for PM2, but too low for BS1 per PAH EP guidelines. No splicing impact is predicted in HSF or MaxEnt (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748923/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: -0.193

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.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.442-18G>A		intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.442-18G>A		intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2	c.442-18G>A		intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1454C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.442-18G>A		intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.538-18G>A		intron_variant	Intron 4 of 5	1
PAH	ENST00000307000.7	c.427-18G>A		intron_variant	Intron 5 of 13	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10781G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251142 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135704

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1455350 Hom.: 2 Cov.: 29 AF XY: 0.000131 AC XY: 95 AN XY: 724452

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000886

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74442

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1 Benign:2

Dec 28, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.442-18G>A variant in PAH has not been reported in the literature to our knowledge. This variant has a MAF of 0.00067 in the gnomAD Latino population. This is too high for PM2, but too low for BS1 per PAH EP guidelines. No splicing impact is predicted in HSF or MaxEnt (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7. -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 19, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.66

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: rs149538764; hg19: chr12-103260459;