12-102855349-A-AAAT

Position:

• chr12-102855349-A-AAAT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000277.3(PAH):​c.510-20_510-18dupATT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,612,404 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.904

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]

PAH (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 12-102855349-A-AAAT is Benign according to our data. Variant chr12-102855349-A-AAAT is described in ClinVar as [Likely_benign]. Clinvar id is 92745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.510-20_510-18dupATT		intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.510-20_510-18dupATT		intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.510-20_510-18dupATT		intron_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.510-20_510-18dupATT		intron_variant		1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.606-20_606-18dupATT		intron_variant		1
PAH	ENST00000307000.7	c.495-20_495-18dupATT		intron_variant		5		ENSP00000303500.2
PAH	ENST00000551988.5	n.531-20_531-18dupATT		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 439 AN: 152186 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000791 AC: 198 AN: 250414 Hom.: 2 AF XY: 0.000591 AC XY: 80 AN XY: 135334

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000348

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: 0.00000884

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000315 AC: 460 AN: 1460100 Hom.: 4 Cov.: 33 AF XY: 0.000286 AC XY: 208 AN XY: 726514

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152304 Hom.: 4 Cov.: 33 AF XY: 0.00312 AC XY: 232 AN XY: 74462

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00149 Hom.: 0

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2023	Variant summary: PAH c.510-20_510-18dupATT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0011 in 281816 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.510-20_510-18dupATT in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Phenylketonuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123293; hg19: chr12-103249127;