12-102886978-G-C

Variant names:

• chr12-102886978-G-C
• rs1522305
• NM_000277.3:c.352+7757C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000277.3(PAH):​c.352+7757C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,136 control chromosomes in the GnomAD database, including 2,525 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2525 hom., cov: 31)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 5 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), G2P, ClinGen, Myriad Women’s Health
• 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

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.352+7757C>G		intron	N/A	NP_000268.1
	PAH	NM_001354304.2		c.352+7757C>G		intron	N/A	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.352+7757C>G		intron	N/A	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.448+7757C>G		intron	N/A
	PAH	ENST00000307000.7	TSL:5	c.337+7757C>G		intron	N/A	ENSP00000303500.2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25686 AN: 152016 Hom.: 2518 Cov.: 31

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0695

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.167

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

GnomAD4 genome AF: 0.169 AC: 25701 AN: 152136 Hom.: 2525 Cov.: 31 AF XY: 0.168 AC XY: 12514 AN XY: 74360

African (AFR) AF: 0.188 AC: 7801 AN: 41492

American (AMR) AF: 0.327 AC: 4991 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3468

East Asian (EAS) AF: 0.0690 AC: 357 AN: 5172

South Asian (SAS) AF: 0.157 AC: 757 AN: 4820

European-Finnish (FIN) AF: 0.0865 AC: 915 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9768 AN: 68012

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.0641 Hom.: 71

Bravo AF: 0.186

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.66
DANN	Benign	0.62
PhyloP100		-0.049
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: rs1522305; hg19: chr12-103280756;