12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-102958393-C-CGCAGCAGCAGCAGCA
• rs3832799
• NM_004316.4:c.172_186dupCAGCAGCAGCAGCAG

Variant summary

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

The NM_004316.4(ASCL1):​c.172_186dupCAGCAGCAGCAGCAG​(p.Gln58_Gln62dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00070 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASCL1 NM_004316.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 0.219
• Publications: 15 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), 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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	NM_004316.4	MANE Select	c.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	NP_004307.2
	PAH	NM_001354304.2		c.-309_-295dupTGCTGCTGCTGCTGC		5_prime_UTR	Exon 1 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000266744.3
	PAH	ENST00000547319.1	TSL:4	n.3_17dupTGCTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-309_-295dupTGCTGCTGCTGCTGC		upstream_gene	N/A	ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 151 AN: 150120 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000876

Gnomad OTH AF: 0.000975

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000702 AC: 952 AN: 1356658 Hom.: 1 Cov.: 17 AF XY: 0.000747 AC XY: 500 AN XY: 669094

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

African (AFR) AF: 0.00133 AC: 38 AN: 28508

American (AMR) AF: 0.00113 AC: 38 AN: 33690

Ashkenazi Jewish (ASJ) AF: 0.0000416 AC: 1 AN: 24016

East Asian (EAS) AF: 0.000509 AC: 17 AN: 33382

South Asian (SAS) AF: 0.000342 AC: 26 AN: 75996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41214

Middle Eastern (MID) AF: 0.000979 AC: 4 AN: 4084

European-Non Finnish (NFE) AF: 0.000746 AC: 790 AN: 1059310

Other (OTH) AF: 0.000673 AC: 38 AN: 56458

⚠️ 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: 0.00101 AC: 151 AN: 150210 Hom.: 0 Cov.: 0 AF XY: 0.00102 AC XY: 75 AN XY: 73326

African (AFR) AF: 0.00190 AC: 78 AN: 40994

American (AMR) AF: 0.000396 AC: 6 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3456

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5054

South Asian (SAS) AF: 0.000630 AC: 3 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000876 AC: 59 AN: 67372

Other (OTH) AF: 0.000965 AC: 2 AN: 2072

Alfa AF: 0.00 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ASCL1-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=79/21	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;