12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCA

Position:

• chr12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004316.4(ASCL1):​c.175_186del​(p.Gln59_Gln62del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000855 in 1,507,074 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: ASCL1 NM_004316.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.809

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 12-102958393-CGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 259284.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102958393-CGCAGCAGCAGCA-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.175_186del	p.Gln59_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-306_-295del		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.175_186del	p.Gln59_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.6_17del		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 222 AN: 150116 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00694

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000683

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000787 AC: 1068 AN: 1356868 Hom.: 2 AF XY: 0.000844 AC XY: 565 AN XY: 669194

Gnomad4 AFR exome AF: 0.00253

Gnomad4 AMR exome AF: 0.000802

Gnomad4 ASJ exome AF: 0.00583

Gnomad4 EAS exome AF: 0.000839

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000541

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00147 AC: 221 AN: 150206 Hom.: 2 Cov.: 0 AF XY: 0.00162 AC XY: 119 AN XY: 73322

Gnomad4 AFR AF: 0.00290

Gnomad4 AMR AF: 0.00119

Gnomad4 ASJ AF: 0.00694

Gnomad4 EAS AF: 0.000396

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000683

Gnomad4 OTH AF: 0.00145

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Phenylketonuria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

ASCL1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;