12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-102958393-CGCA-C
• rs3832799
• NM_004316.4:c.184_186delCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004316.4(ASCL1):​c.184_186delCAG​(p.Gln62del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,297,614 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., cov: 0)
  • Exomes 𝑓: 0.026 (39 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.219

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 12-102958393-CGCA-C is Benign according to our data. Variant chr12-102958393-CGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 227179.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102958393-CGCA-C is described in Lovd as [Benign]. Variant chr12-102958393-CGCA-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.184_186delCAG	p.Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-297_-295delTGC		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCL1	ENST00000266744.4	c.184_186delCAG	p.Gln62del	conservative_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000547319.1	n.15_17delTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5	c.-297_-295delTGC		upstream_gene_variant		3		ENSP00000447620.1
PAH	ENST00000635500.1	n.-174_-172delTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1587 AN: 149932 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00893

Gnomad ASJ AF: 0.00492

Gnomad EAS AF: 0.00355

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.00827

Gnomad OTH AF: 0.0137

GnomAD4 exome AF: 0.0257 AC: 29494 AN: 1147600 Hom.: 39 AF XY: 0.0276 AC XY: 15525 AN XY: 562096

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.0558

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.0334

Gnomad4 SAS exome AF: 0.0808

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0106 AC: 1589 AN: 150014 Hom.: 7 Cov.: 0 AF XY: 0.0113 AC XY: 831 AN XY: 73218

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00892

Gnomad4 ASJ AF: 0.00492

Gnomad4 EAS AF: 0.00357

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00828

Gnomad4 OTH AF: 0.0141

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln51[11] in exon 1 of ASCL1: This variant is not expected to have clinical sign ificance because it has been identified in 2.2% (7/322) of Caucasian control chr omosomes (Deng 2010) and has been identified by our laboratory in 1.6% (5/304) o f Caucasian control chromosomes. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;