12-102958345-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004316.4(ASCL1):ā€‹c.101C>Gā€‹(p.Thr34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Synonymous variant affecting the same amino acid position (i.e. TAAAA34T) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000067 ( 0 hom., cov: 32)
Exomes š‘“: 7.8e-7 ( 0 hom. )

Consequence

ASCL1
NM_004316.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15044987).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ASCL1NM_004316.4 linkuse as main transcriptc.101C>G p.Thr34Arg missense_variant 1/2 ENST00000266744.4
PAHNM_001354304.2 linkuse as main transcriptc.-246G>C 5_prime_UTR_variant 1/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ASCL1ENST00000266744.4 linkuse as main transcriptc.101C>G p.Thr34Arg missense_variant 1/21 NM_004316.4 P1
PAHENST00000551337.5 linkuse as main transcriptc.-246G>C 5_prime_UTR_variant 1/53
PAHENST00000547319.1 linkuse as main transcriptn.66G>C non_coding_transcript_exon_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.00000666
AC:
1
AN:
150182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.77e-7
AC:
1
AN:
1286306
Hom.:
0
Cov.:
29
AF XY:
0.00000158
AC XY:
1
AN XY:
633450
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.69e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000666
AC:
1
AN:
150182
Hom.:
0
Cov.:
32
AF XY:
0.0000136
AC XY:
1
AN XY:
73342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.40
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.56
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
0.98
N
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.87
N
REVEL
Benign
0.066
Sift
Uncertain
0.026
D
Sift4G
Benign
0.37
T
Polyphen
0.032
B
Vest4
0.39
MutPred
0.24
Gain of methylation at T34 (P = 0.0037);
MVP
0.39
MPC
1.1
ClinPred
0.24
T
GERP RS
3.5
Varity_R
0.31
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1428646714; hg19: chr12-103352123; API