12-102958345-C-G

Variant names:

• chr12-102958345-C-G
• rs1428646714
• NM_004316.4:c.101C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354304.2(PAH):​c.-246G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PAH NM_001354304.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 1 publications found

Genes affected

ASCL1 (HGNC:738): (achaete-scute family bHLH transcription factor 1) This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15044987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354304.2. 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
	ASCL1	NM_004316.4	MANE Select	c.101C>G	p.Thr34Arg	missense	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-246G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001341233.1	P00439
	PAH	NM_001354304.2		c.-246G>C		5_prime_UTR	Exon 1 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.101C>G	p.Thr34Arg	missense	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000551337.5	TSL:3	c.-246G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000447620.1	F8W0A0
	PAH	ENST00000551337.5	TSL:3	c.-246G>C		5_prime_UTR	Exon 1 of 5	ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1286306 Hom.: 0 Cov.: 29 AF XY: 0.00000158 AC XY: 1 AN XY: 633450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24420

American (AMR) AF: 0.00 AC: 0 AN: 19562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21650

East Asian (EAS) AF: 0.00 AC: 0 AN: 28140

South Asian (SAS) AF: 0.00 AC: 0 AN: 64930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3864

European-Non Finnish (NFE) AF: 9.69e-7 AC: 1 AN: 1032358

Other (OTH) AF: 0.00 AC: 0 AN: 52792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150182 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73342

African (AFR) AF: 0.00 AC: 0 AN: 40132

American (AMR) AF: 0.00 AC: 0 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67738

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.066
Sift	Uncertain	0.026	D
Sift4G	Benign	0.37	T
Polyphen		0.032	B
Vest4		0.39
MutPred		0.24		Gain of methylation at T34 (P = 0.0037)
MVP		0.39
MPC		1.1
ClinPred		0.24	T
GERP RS		3.5
PromoterAI		0.048	Neutral
Varity_R		0.31
gMVP		0.58
Mutation Taster		=85/15	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: rs1428646714; hg19: chr12-103352123;