12-102958365-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004316.4(ASCL1):c.121G>C(p.Ala41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,439,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A41S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

ASCL1
NM_004316.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

0 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), ClinGen, Myriad Women’s Health, G2P
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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3255988).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004316.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	NM_004316.4	MANE Select	c.121G>C	p.Ala41Pro	missense	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-266C>G		5_prime_UTR	Exon 1 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.121G>C	p.Ala41Pro	missense	Exon 1 of 2	ENSP00000266744.3	P50553
PAH	ENST00000551337.5	TSL:3	c.-266C>G		5_prime_UTR	Exon 1 of 5	ENSP00000447620.1	F8W0A0
PAH	ENST00000547319.1	TSL:4	n.46C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151356

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000172

AC:

AN:

57982

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000117

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000233

AC:

AN:

1287710

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

634204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25074

American (AMR)

AF:

0.00

AC:

AN:

18224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21216

East Asian (EAS)

AF:

0.00

AC:

AN:

28210

South Asian (SAS)

AF:

0.00

AC:

AN:

64808

European-Finnish (FIN)

AF:

0.0000251

AC:

AN:

39892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3838

European-Non Finnish (NFE)

AF:

0.00000193

AC:

AN:

1033688

Other (OTH)

AF:

0.00

AC:

AN:

52760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41104

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000953

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67842

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

1.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.51

REVEL

Benign

0.11

Sift

Uncertain

0.010

Sift4G

Uncertain

0.038

Polyphen

0.94

Vest4

0.37

MutPred

0.30

Gain of glycosylation at A41 (P = 0.0049)

MVP

0.82

MPC

1.3

ClinPred

0.24

GERP RS

3.2

PromoterAI

-0.0054

Neutral

(source)

Varity_R

0.29

gMVP

0.57

Mutation Taster

=74/26

polymorphism

(source)

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over