chr12-102847410-A-G

Variant names:

• chr12-102847410-A-G
• rs1718312
• NM_000277.3:c.913-459T>C

Variant summary

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

The NM_000277.3(PAH):​c.913-459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 186,186 control chromosomes in the GnomAD database, including 10,089 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 0.32 (8223 hom., cov: 32)
  • Exomes 𝑓: 0.31 (1866 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.935
• Publications: 3 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.913-459T>C		intron_variant	Intron 8 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.913-459T>C		intron_variant	Intron 9 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.913-459T>C		intron_variant	Intron 8 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48423 AN: 151954 Hom.: 8218 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.306 AC: 10450 AN: 34114 Hom.: 1866 Cov.: 0 AF XY: 0.303 AC XY: 5312 AN XY: 17546

African (AFR) AF: 0.207 AC: 320 AN: 1546

American (AMR) AF: 0.261 AC: 941 AN: 3602

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 203 AN: 768

East Asian (EAS) AF: 0.0448 AC: 140 AN: 3128

South Asian (SAS) AF: 0.301 AC: 976 AN: 3244

European-Finnish (FIN) AF: 0.350 AC: 286 AN: 816

Middle Eastern (MID) AF: 0.207 AC: 24 AN: 116

European-Non Finnish (NFE) AF: 0.364 AC: 6998 AN: 19226

Other (OTH) AF: 0.337 AC: 562 AN: 1668

GnomAD4 genome AF: 0.319 AC: 48444 AN: 152072 Hom.: 8223 Cov.: 32 AF XY: 0.321 AC XY: 23831 AN XY: 74352

African (AFR) AF: 0.234 AC: 9716 AN: 41506

American (AMR) AF: 0.275 AC: 4203 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 973 AN: 3470

East Asian (EAS) AF: 0.0533 AC: 276 AN: 5182

South Asian (SAS) AF: 0.300 AC: 1445 AN: 4816

European-Finnish (FIN) AF: 0.427 AC: 4500 AN: 10548

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26137 AN: 67956

Other (OTH) AF: 0.328 AC: 693 AN: 2110

Alfa AF: 0.350 Hom.: 39388

Bravo AF: 0.303

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.62
DANN	Benign	0.32
PhyloP100		-0.94
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: rs1718312; hg19: chr12-103241188;