12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-102958393-C-CGCAGCAGCAGCAGCA
• rs3832799
• NM_004316.4:c.172_186dupCAGCAGCAGCAGCAG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004316.4(ASCL1):​c.172_186dupCAGCAGCAGCAGCAG​(p.Gln58_Gln62dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00070 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASCL1 NM_004316.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 0.219

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-309_-295dupTGCTGCTGCTGCTGC		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.172_186dupCAGCAGCAGCAGCAG	p.Gln58_Gln62dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000547319.1	n.3_17dupTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000551337.5	c.-309_-295dupTGCTGCTGCTGCTGC		upstream_gene_variant		3		ENSP00000447620.1
PAH	ENST00000635500.1	n.-186_-172dupTGCTGCTGCTGCTGC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 151 AN: 150120 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000876

Gnomad OTH AF: 0.000975

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000702 AC: 952 AN: 1356658 Hom.: 1 Cov.: 17 AF XY: 0.000747 AC XY: 500 AN XY: 669094

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.0000416

Gnomad4 EAS exome AF: 0.000509

Gnomad4 SAS exome AF: 0.000342

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00101 AC: 151 AN: 150210 Hom.: 0 Cov.: 0 AF XY: 0.00102 AC XY: 75 AN XY: 73326

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000396

Gnomad4 SAS AF: 0.000630

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000876

Gnomad4 OTH AF: 0.000965

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln51[17] variant in ASCL1 (alternate gene names: MASH1 or HASH1) represents one of several alleles of a poly-glutamine tract of variable length. The Gln51[ 12] allele represents the reference sequence (hg19). This variant has been ident ified by our laboratory in one Caucasian individual with pulmonary fibrosis (LMM unpublished data). In addition, this variant has also been reported in 0.1% (1/ 1604) of Japanese control chromosomes (Ide 2005) and in 0.3% (1/304) of Caucasia n control chromosomes tested by our laboratory. Computational prediction tools a nd conservation analysis are limited or unavailable for this variant. In summary , the clinical significance of the Gln51[17] variant is uncertain. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ASCL1-related disorder Benign:1

Feb 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;