12-102958378-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004316.4(ASCL1):c.134C>T(p.Ala45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,478,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ASCL1
NM_004316.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014244646).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.134C>T	p.Ala45Val	missense_variant	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-279G>A		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.134C>T	p.Ala45Val	missense_variant	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000547319.1 link	n.33G>A		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5 link	c.-279G>A		upstream_gene_variant		3		ENSP00000447620.1	F8W0A0
PAH	ENST00000635500.1 link	n.-156G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

149798

Hom.:

Cov.:

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:

0.00139

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

81802

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

46806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00391

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1329044

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

655318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000408

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000364

GnomAD4 genome

AF:

0.0000467

AC:

AN:

149904

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00139

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.000101

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134C>T (p.A45V) alteration is located in exon 1 (coding exon 1) of the ASCL1 gene. This alteration results from a C to T substitution at nucleotide position 134, causing the alanine (A) at amino acid position 45 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.55

M_CAP

Benign

0.084

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.18

REVEL

Benign

0.11

Sift

Uncertain

0.018

Sift4G

Benign

0.24

Polyphen

0.016

Vest4

0.38

MutPred

0.28

Gain of catalytic residue at A45 (P = 0.021);

MVP

0.41

MPC

1.0

ClinPred

0.094

GERP RS

4.1

Varity_R

0.17

gMVP

0.30

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.

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