12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

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

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.219

Publications

15 publications found

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 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

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-309_-295dupTGCTGCTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASCL1	ENST00000266744.4 link	c.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.3_17dupTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-309_-295dupTGCTGCTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-186_-172dupTGCTGCTGCTGCTGC		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

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

African (AFR)

AF:

0.00133

AC:

AN:

28508

American (AMR)

AF:

0.00113

AC:

AN:

33690

Ashkenazi Jewish (ASJ)

AF:

0.0000416

AC:

AN:

24016

East Asian (EAS)

AF:

0.000509

AC:

AN:

33382

South Asian (SAS)

AF:

0.000342

AC:

AN:

75996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41214

Middle Eastern (MID)

AF:

0.000979

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.000746

AC:

790

AN:

1059310

Other (OTH)

AF:

0.000673

AC:

AN:

56458

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00101

AC:

151

AN:

150210

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

73326

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

40994

American (AMR)

AF:

0.000396

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3456

East Asian (EAS)

AF:

0.000396

AC:

AN:

5054

South Asian (SAS)

AF:

0.000630

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000876

AC:

AN:

67372

Other (OTH)

AF:

0.000965

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

277

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

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ASCL1-related disorder

Benign:1

Feb 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

PhyloP100

0.22

Mutation Taster

=79/21

polymorphism

(source)

Splicing

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

Publications

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12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over