NM_000277.3:c.*772_*775delGTAA

Variant names:

• chr12-102838399-TTTAC-T
• rs551502562
• NM_000277.3:c.*772_*775delGTAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000277.3(PAH):​c.*772_*775delGTAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 152,338 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). The gene PAH is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0059 (9 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: PAH NM_000277.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.129
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00595 (906/152338) while in subpopulation AFR AF = 0.0192 (799/41576). AF 95% confidence interval is 0.0181. There are 9 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.*772_*775delGTAA		3_prime_UTR	Exon 13 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.*772_*775delGTAA		3_prime_UTR	Exon 14 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.*772_*775delGTAA		3_prime_UTR	Exon 13 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.*772_*775delGTAA		3_prime_UTR	Exon 14 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.*772_*775delGTAA		3_prime_UTR	Exon 13 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 906 AN: 152220 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

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: 0.000412

Gnomad OTH AF: 0.00621

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00595 AC: 906 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74502

African (AFR) AF: 0.0192 AC: 799 AN: 41576

American (AMR) AF: 0.00418 AC: 64 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68026

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00619 Hom.: 0

Bravo AF: 0.00701

Asia WGS AF: 0.00202 AC: 8 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs551502562; hg19: chr12-103232177;