Genetic Variant ASCL1:p.Ala39_Ala43del (chr12-102958344-ACGGCCGCAGCCGCGG-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_004316.4(ASCL1):c.114_128delGGCGGCCGCAGCCGC(p.Ala39_Ala43del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,452,160 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 39 hom. )

Consequence

ASCL1
NM_004316.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.34

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004316.4

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00151 (1968/1300622) while in subpopulation AFR AF= 0.0185 (477/25762). AF 95% confidence interval is 0.0171. There are 39 homozygotes in gnomad4_exome. There are 960 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 773 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.114_128delGGCGGCCGCAGCCGC	p.Ala39_Ala43del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-260_-246delCCGCGGCTGCGGCCG		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.114_128delGGCGGCCGCAGCCGC	p.Ala39_Ala43del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000551337.5 link	c.-260_-246delCCGCGGCTGCGGCCG		5_prime_UTR_variant	Exon 1 of 5	3		ENSP00000447620.1	F8W0A0
PAH	ENST00000547319.1 link	n.52_66delCCGCGGCTGCGGCCG		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000635500.1 link	n.-137_-123delCCGCGGCTGCGGCCG		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00512

AC:

775

AN:

151432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00460

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.000382

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00241

GnomAD3 exomes

AF:

0.00222

AC:

150

AN:

67458

Hom.:

AF XY:

0.00245

AC XY:

AN XY:

39616

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00238

Gnomad FIN exome

AF:

0.000489

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00322

GnomAD4 exome

AF:

0.00151

AC:

1968

AN:

1300622

Hom.:

AF XY:

0.00150

AC XY:

960

AN XY:

640824

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.00413

Gnomad4 ASJ exome

AF:

0.000271

Gnomad4 EAS exome

AF:

0.000565

Gnomad4 SAS exome

AF:

0.00211

Gnomad4 FIN exome

AF:

0.000332

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00510

AC:

773

AN:

151538

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

385

AN XY:

74078

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.00459

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.000590

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.000382

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.00549

Asia WGS

AF:

0.00174

AC:

AN:

3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital central hypoventilation

Uncertain:1

Dec 01, 2003

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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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