rs10860935

Variant names:

• chr12-102889153-T-A
• rs10860935
• NM_000277.3:c.352+5582A>T

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+5582A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,028 control chromosomes in the GnomAD database, including 3,102 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 0.18 (3102 hom., cov: 31)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• 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

LOC124902999 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.352+5582A>T		intron_variant	Intron 3 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.352+5582A>T		intron_variant	Intron 4 of 13		NP_001341233.1
PAH	XM_017019370.2	c.352+5582A>T		intron_variant	Intron 3 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.862+9220T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.352+5582A>T		intron_variant	Intron 3 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27724 AN: 151910 Hom.: 3088 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.183 AC: 27779 AN: 152028 Hom.: 3102 Cov.: 31 AF XY: 0.178 AC XY: 13256 AN XY: 74326

African (AFR) AF: 0.316 AC: 13098 AN: 41430

American (AMR) AF: 0.122 AC: 1869 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3466

East Asian (EAS) AF: 0.138 AC: 715 AN: 5166

South Asian (SAS) AF: 0.0868 AC: 418 AN: 4818

European-Finnish (FIN) AF: 0.0895 AC: 946 AN: 10572

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9656 AN: 67976

Other (OTH) AF: 0.176 AC: 372 AN: 2108

Alfa AF: 0.162 Hom.: 294

Bravo AF: 0.194

Asia WGS AF: 0.120 AC: 418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.078
DANN	Benign	0.72
PhyloP100		-1.3
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: rs10860935; hg19: chr12-103282931;