Variant chr12-102958393-C-CGCAGCAGCAGCAGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004316.4(ASCL1):c.172_186dup(p.Gln58_Gln62dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. 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 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 0.219

Variant links:

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]

ASCL1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4 linkuse as main transcript	c.172_186dup	p.Gln58_Gln62dup	inframe_insertion	1/2	ENST00000266744.4
PAH	NM_001354304.2 linkuse as main transcript	c.-295_-294insTGCTGCTGCTGCTGC		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ASCL1	ENST00000266744.4 linkuse as main transcript	c.172_186dup	p.Gln58_Gln62dup	inframe_insertion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1 linkuse as main transcript	n.17_18insTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

151

AN:

150120

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000747

AC XY:

500

AN XY:

669094

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.00113

Gnomad4 ASJ exome

AF:

0.0000416

Gnomad4 EAS exome

AF:

0.000509

Gnomad4 SAS exome

AF:

0.000342

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000746

Gnomad4 OTH exome

AF:

0.000673

GnomAD4 genome

AF:

0.00101

AC:

151

AN:

150210

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

73326

show subpopulations

Gnomad4 AFR

AF:

0.00190

Gnomad4 AMR

AF:

0.000396

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000396

Gnomad4 SAS

AF:

0.000630

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000876

Gnomad4 OTH

AF:

0.000965

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2014

The Gln51[17] variant in ASCL1 (alternate gene names: MASH1 or HASH1) represents one of several alleles of a poly-glutamine tract of variable length. The Gln51[ 12] allele represents the reference sequence (hg19). This variant has been ident ified by our laboratory in one Caucasian individual with pulmonary fibrosis (LMM unpublished data). In addition, this variant has also been reported in 0.1% (1/ 1604) of Japanese control chromosomes (Ide 2005) and in 0.3% (1/304) of Caucasia n control chromosomes tested by our laboratory. Computational prediction tools a nd conservation analysis are limited or unavailable for this variant. In summary , the clinical significance of the Gln51[17] variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ASCL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over