12-102958393-C-CGCAGCAGCAGCA

Position:

• chr12-102958393-C-CGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004316.4(ASCL1):​c.175_186dup​(p.Gln59_Gln62dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (35 hom., cov: 0)
  • Exomes 𝑓: 0.0092 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASCL1 NM_004316.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 -9 ACMG points.

• BP6: Variant 12-102958393-C-CGCAGCAGCAGCA is Benign according to our data. Variant chr12-102958393-C-CGCAGCAGCAGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228442.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0157 (2353/150196) while in subpopulation AFR AF= 0.0337 (1383/40988). AF 95% confidence interval is 0.0323. There are 35 homozygotes in gnomad4. There are 1104 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.175_186dup	p.Gln59_Gln62dup	inframe_insertion	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-295_-294insTGCTGCTGCTGC		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.175_186dup	p.Gln59_Gln62dup	inframe_insertion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.17_18insTGCTGCTGCTGC		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2357 AN: 150106 Hom.: 35 Cov.: 0

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00483

Gnomad FIN AF: 0.00148

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.00939

Gnomad OTH AF: 0.00926

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00919 AC: 12466 AN: 1356242 Hom.: 12 Cov.: 17 AF XY: 0.00896 AC XY: 5996 AN XY: 668922

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00725

Gnomad4 SAS exome AF: 0.00480

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00895

Gnomad4 OTH exome AF: 0.00921

GnomAD4 genome AF: 0.0157 AC: 2353 AN: 150196 Hom.: 35 Cov.: 0 AF XY: 0.0151 AC XY: 1104 AN XY: 73316

Gnomad4 AFR AF: 0.0337

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0109

Gnomad4 SAS AF: 0.00483

Gnomad4 FIN AF: 0.00148

Gnomad4 NFE AF: 0.00940

Gnomad4 OTH AF: 0.00869

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 25, 2014	Variant classified as Uncertain Significance - Favor Benign. The Gln51[16] varia nt in ASCL1 (alternate gene names: MASH1 or HASH1) represents one of several all eles of a poly-glutamine tract of variable length. The Gln51[12] allele represen ts the reference sequence (hg19). This variant has not been previously reported in individuals with pulmonary disease, but has been reported in 0.7% (11/1604) o f Japanese control chromosomes (Ide 2005). Computational prediction tools and co nservation analysis are limited or unavailable for this variant. In summary, whi le the clinical significance of the Gln51[16] variant is uncertain, its frequenc y suggests that it is more likely to be benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

ASCL1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2020

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;