rs558732328

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004316.4(ASCL1):c.123A>G(p.Ala41Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,441,078 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 5 hom., cov: 33)

Exomes 𝑓: 0.012 ( 115 hom. )

Consequence

ASCL1
NM_004316.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.10

Publications

1 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), G2P, ClinGen, Myriad Women’s Health
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: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-102958367-A-G is Benign according to our data. Variant chr12-102958367-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.11 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	NM_004316.4	MANE Select	c.123A>G	p.Ala41Ala	synonymous	Exon 1 of 2	NP_004307.2
	PAH	NM_001354304.2		c.-268T>C		5_prime_UTR	Exon 1 of 14	NP_001341233.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.123A>G	p.Ala41Ala	synonymous	Exon 1 of 2	ENSP00000266744.3
PAH	ENST00000547319.1	TSL:4	n.44T>C		non_coding_transcript_exon	Exon 1 of 3
PAH	ENST00000551337.5	TSL:3	c.-268T>C		upstream_gene	N/A	ENSP00000447620.1

Frequencies

GnomAD3 genomes

AF:

0.00684

AC:

1034

AN:

151206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00322

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00172

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.00481

GnomAD2 exomes

AF:

0.00412

AC:

245

AN:

59536

AF XY:

0.00430

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.000415

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00113

Gnomad NFE exome

AF:

0.00897

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.0117

AC:

15086

AN:

1289764

Hom.:

115

Cov.:

AF XY:

0.0114

AC XY:

7240

AN XY:

635256

show subpopulations

African (AFR)

AF:

0.00187

AC:

AN:

25100

American (AMR)

AF:

0.00217

AC:

AN:

18458

Ashkenazi Jewish (ASJ)

AF:

0.0000937

AC:

AN:

21334

East Asian (EAS)

AF:

0.00

AC:

AN:

28256

South Asian (SAS)

AF:

0.00156

AC:

102

AN:

65244

European-Finnish (FIN)

AF:

0.00211

AC:

AN:

40258

Middle Eastern (MID)

AF:

0.00390

AC:

AN:

3850

European-Non Finnish (NFE)

AF:

0.0140

AC:

14453

AN:

1034434

Other (OTH)

AF:

0.00647

AC:

342

AN:

52830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

947

1893

2840

3786

4733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.00683

AC:

1034

AN:

151314

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

460

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.00241

AC:

AN:

41122

American (AMR)

AF:

0.00322

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00104

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0125

AC:

850

AN:

67808

Other (OTH)

AF:

0.00476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00783

Hom.:

Bravo

AF:

0.00687

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

ASCL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.8

(source)

DANN

Benign

0.21

PhyloP100

-1.1

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over