rs552552603

Variant names:

• chr12-102958382-A-T
• rs552552603
• NM_004316.4:c.138A>T

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.138A>T​(p.Ala46Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,470,852 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (37 hom.)
• Consequence: ASCL1 NM_004316.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.34

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=-0.78).
• BP6: Variant 12-102958382-A-T is Benign according to our data. Variant chr12-102958382-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 227178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS2: High AC in GnomAd4 at 674 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.138A>T	p.Ala46Ala	synonymous_variant	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-283T>A		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCL1	ENST00000266744.4	c.138A>T	p.Ala46Ala	synonymous_variant	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000547319.1	n.29T>A		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5	c.-283T>A		upstream_gene_variant		3		ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 674 AN: 148132 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0111

Gnomad AMR AF: 0.00887

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00446

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00618

Gnomad OTH AF: 0.00439

GnomAD3 exomes AF: 0.00475 AC: 399 AN: 84078 Hom.: 0 AF XY: 0.00431 AC XY: 207 AN XY: 47986

Gnomad AFR exome AF: 0.00335

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.00768

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00638 AC: 8441 AN: 1322612 Hom.: 37 Cov.: 29 AF XY: 0.00614 AC XY: 4001 AN XY: 652032

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00643

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.00282

Gnomad4 NFE exome AF: 0.00738

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00455 AC: 674 AN: 148240 Hom.: 3 Cov.: 33 AF XY: 0.00439 AC XY: 318 AN XY: 72480

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00886

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000426

Gnomad4 FIN AF: 0.00446

Gnomad4 NFE AF: 0.00618

Gnomad4 OTH AF: 0.00434

Alfa AF: 0.00459 Hom.: 2

Bravo AF: 0.00505

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ASCL1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 02, 2015

p.Ala46Ala 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. It has been identified in 0.2% (5/2136) of Eu ropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs552552603). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.9
DANN	Benign	0.59

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: rs552552603; hg19: chr12-103352160;