12-102855146-C-T

Variant names:

• chr12-102855146-C-T
• rs1126758
• NM_000277.3:c.696G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000277.3(PAH):​c.696G>A​(p.Gln232Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 1,612,432 control chromosomes in the GnomAD database, including 297,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene PAH is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.64 (32291 hom., cov: 33)
  • Exomes 𝑓: 0.60 (265563 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.59
• Publications: 38 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-102855146-C-T is Benign according to our data. Variant chr12-102855146-C-T is described in ClinVar as Benign. ClinVar VariationId is 167414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

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.696G>A	p.Gln232Gln	synonymous	Exon 6 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.696G>A	p.Gln232Gln	synonymous	Exon 7 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.696G>A	p.Gln232Gln	synonymous	Exon 6 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.792G>A		non_coding_transcript_exon	Exon 6 of 6
	PAH	ENST00000906695.1		c.696G>A	p.Gln232Gln	synonymous	Exon 6 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96994 AN: 151978 Hom.: 32266 Cov.: 33

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.580 AC: 145665 AN: 251250 AF XY: 0.573

Gnomad AFR exome AF: 0.778

Gnomad AMR exome AF: 0.704

Gnomad ASJ exome AF: 0.547

Gnomad EAS exome AF: 0.0903

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.595 AC: 869087 AN: 1460334 Hom.: 265563 Cov.: 37 AF XY: 0.593 AC XY: 430734 AN XY: 726546

African (AFR) AF: 0.780 AC: 26093 AN: 33454

American (AMR) AF: 0.704 AC: 31469 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 14180 AN: 26116

East Asian (EAS) AF: 0.0907 AC: 3599 AN: 39696

South Asian (SAS) AF: 0.570 AC: 49121 AN: 86226

European-Finnish (FIN) AF: 0.602 AC: 32154 AN: 53410

Middle Eastern (MID) AF: 0.558 AC: 3216 AN: 5766

European-Non Finnish (NFE) AF: 0.607 AC: 674085 AN: 1110592

Other (OTH) AF: 0.583 AC: 35170 AN: 60354

GnomAD4 genome AF: 0.638 AC: 97075 AN: 152098 Hom.: 32291 Cov.: 33 AF XY: 0.638 AC XY: 47427 AN XY: 74368

African (AFR) AF: 0.774 AC: 32096 AN: 41482

American (AMR) AF: 0.691 AC: 10558 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1892 AN: 3470

East Asian (EAS) AF: 0.0948 AC: 491 AN: 5180

South Asian (SAS) AF: 0.555 AC: 2675 AN: 4816

European-Finnish (FIN) AF: 0.610 AC: 6456 AN: 10582

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40960 AN: 67970

Other (OTH) AF: 0.623 AC: 1315 AN: 2112

Alfa AF: 0.621 Hom.: 27295

Bravo AF: 0.646

Asia WGS AF: 0.397 AC: 1382 AN: 3478

EpiCase AF: 0.587

EpiControl AF: 0.591

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Phenylketonuria (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.27
DANN	Benign	0.50
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs1126758; hg19: chr12-103248924; COSMIC: COSV61015935; COSMIC: COSV61015935;