12-102958344-ACGGCCGCAGCCGCGG-A

Variant summary

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

The NM_004316.4(ASCL1):​c.114_128del​(p.Ala43_Ala47del) variant causes a 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). Synonymous variant affecting the same amino acid position (i.e. TAAAA34T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 39 hom. )

Consequence

ASCL1
NM_004316.4 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]
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]

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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/exons MANE UniProt
ASCL1NM_004316.4 linkuse as main transcriptc.114_128del p.Ala43_Ala47del inframe_deletion 1/2 ENST00000266744.4
PAHNM_001354304.2 linkuse as main transcriptc.-260_-246del 5_prime_UTR_variant 1/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ASCL1ENST00000266744.4 linkuse as main transcriptc.114_128del p.Ala43_Ala47del inframe_deletion 1/21 NM_004316.4 P1
PAHENST00000551337.5 linkuse as main transcriptc.-260_-246del 5_prime_UTR_variant 1/53
PAHENST00000547319.1 linkuse as main transcriptn.52_66del non_coding_transcript_exon_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.00512
AC:
775
AN:
151432
Hom.:
2
Cov.:
32
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.:
14
AF XY:
0.00245
AC XY:
97
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.:
39
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.:
2
Cov.:
32
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.:
0
Bravo
AF:
0.00549
Asia WGS
AF:
0.00174
AC:
6
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
Uncertain significance, no assertion criteria providedliterature onlyOMIMDec 01, 2003- -

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.

Other links and lift over

dbSNP: rs533680685; hg19: chr12-103352122; API