12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004316.4(ASCL1):c.175_186dupCAGCAGCAGCAG(p.Gln59_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 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 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

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: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].

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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.175_186dupCAGCAGCAGCAG	p.Gln59_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-306_-295dupTGCTGCTGCTGC		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.175_186dupCAGCAGCAGCAG	p.Gln59_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.6_17dupTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-306_-295dupTGCTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-183_-172dupTGCTGCTGCTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2357

AN:

150106

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00896

AC XY:

5996

AN XY:

668922

show subpopulations

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

African (AFR)

AF:

0.0333

AC:

949

AN:

28464

American (AMR)

AF:

0.0142

AC:

479

AN:

33690

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

339

AN:

23998

East Asian (EAS)

AF:

0.00725

AC:

242

AN:

33372

South Asian (SAS)

AF:

0.00480

AC:

365

AN:

75984

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

41214

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00895

AC:

9477

AN:

1058988

Other (OTH)

AF:

0.00921

AC:

520

AN:

56448

⚠️ 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: 0.399

Heterozygous variant carriers

503

1006

1508

2011

2514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0157

AC:

2353

AN:

150196

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1104

AN XY:

73316

show subpopulations

African (AFR)

AF:

0.0337

AC:

1383

AN:

40988

American (AMR)

AF:

0.0112

AC:

169

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3456

East Asian (EAS)

AF:

0.0109

AC:

AN:

5054

South Asian (SAS)

AF:

0.00483

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00940

AC:

633

AN:

67370

Other (OTH)

AF:

0.00869

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00485

Hom.:

277

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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. -

Sep 14, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ASCL1-related disorder

Benign:1

Jul 01, 2020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

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