chr12-102958382-A-C

Variant names:

• chr12-102958382-A-C
• rs552552603
• NM_004316.4:c.138A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004316.4(ASCL1):​c.138A>C​(p.Ala46Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,322,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A46A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ASCL1 NM_004316.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004316.4. 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.138A>C	p.Ala46Ala	synonymous	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-283T>G		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.138A>C	p.Ala46Ala	synonymous	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000547319.1	TSL:4	n.29T>G		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-283T>G		upstream_gene	N/A	ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1322624 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 652036

African (AFR) AF: 0.00 AC: 0 AN: 25106

American (AMR) AF: 0.00 AC: 0 AN: 26610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22646

East Asian (EAS) AF: 0.00 AC: 0 AN: 28948

South Asian (SAS) AF: 0.00 AC: 0 AN: 71204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1046536

Other (OTH) AF: 0.00 AC: 0 AN: 54630

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.1
DANN	Benign	0.42
PhyloP100		-2.3
PromoterAI		0.012	Neutral

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: rs552552603; hg19: chr12-103352160;