rs558732328

chr12-102958367-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004316.4(ASCL1):c.123A>G(p.Ala41=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.10

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 AC in GnomAd at 1034 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.123A>G	p.Ala41=	synonymous_variant	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-268T>C		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.123A>G	p.Ala41=	synonymous_variant	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1	n.44T>C		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00684 AC: 1034 AN: 151206 Hom.: 5 Cov.: 33

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

GnomAD3 exomes AF: 0.00412 AC: 245 AN: 59536 Hom.: 3 AF XY: 0.00430 AC XY: 152 AN XY: 35370

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 SAS exome AF: 0.000902

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.: 29 AF XY: 0.0114 AC XY: 7240 AN XY: 635256

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.0000937

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.00211

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.00683 AC: 1034 AN: 151314 Hom.: 5 Cov.: 33 AF XY: 0.00622 AC XY: 460 AN XY: 73974

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00322

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00172

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00783 Hom.: 1

Bravo AF: 0.00687

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2015	p.Ala41Ala in exon 1 of ASCL1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

ASCL1: BP4, BP7, BS1, BS2 -

ASCL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.8
Dann	Benign	0.21

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

Other links and lift over

dbSNP: rs558732328; hg19: chr12-103352145;