NM_004316.4:c.172_186delCAGCAGCAGCAGCAG

Variant names:

• chr12-102958393-CGCAGCAGCAGCAGCA-C
• rs3832799
• NM_004316.4:c.172_186delCAGCAGCAGCAGCAG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004316.4(ASCL1):​c.172_186delCAGCAGCAGCAGCAG​(p.Gln58_Gln62del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,507,022 control chromosomes in the GnomAD database, including 10 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (9 hom.)
• Consequence: ASCL1 NM_004316.4 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:5
• Conservation: PhyloP100: 0.809
• Publications: 15 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-102958393-CGCAGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCAGCA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 193277.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.172_186delCAGCAGCAGCAGCAG	p.Gln58_Gln62del	conservative_inframe_deletion	Exon 1 of 2	NP_004307.2
	PAH	NM_001354304.2		c.-309_-295delTGCTGCTGCTGCTGC		5_prime_UTR	Exon 1 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.172_186delCAGCAGCAGCAGCAG	p.Gln58_Gln62del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000266744.3
	PAH	ENST00000547319.1	TSL:4	n.3_17delTGCTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-309_-295delTGCTGCTGCTGCTGC		upstream_gene	N/A	ENSP00000447620.1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 437 AN: 150120 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00377

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00273

Gnomad FIN AF: 0.000985

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00292

GnomAD4 exome AF: 0.00435 AC: 5896 AN: 1356812 Hom.: 9 AF XY: 0.00423 AC XY: 2831 AN XY: 669150

African (AFR) AF: 0.00123 AC: 35 AN: 28512

American (AMR) AF: 0.00452 AC: 152 AN: 33664

Ashkenazi Jewish (ASJ) AF: 0.000208 AC: 5 AN: 24016

East Asian (EAS) AF: 0.0000300 AC: 1 AN: 33382

South Asian (SAS) AF: 0.00323 AC: 245 AN: 75966

European-Finnish (FIN) AF: 0.00119 AC: 49 AN: 41206

Middle Eastern (MID) AF: 0.000979 AC: 4 AN: 4084

European-Non Finnish (NFE) AF: 0.00490 AC: 5192 AN: 1059520

Other (OTH) AF: 0.00377 AC: 213 AN: 56462

GnomAD4 genome AF: 0.00291 AC: 437 AN: 150210 Hom.: 1 Cov.: 0 AF XY: 0.00288 AC XY: 211 AN XY: 73326

African (AFR) AF: 0.00154 AC: 63 AN: 40994

American (AMR) AF: 0.00376 AC: 57 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00273 AC: 13 AN: 4762

European-Finnish (FIN) AF: 0.000985 AC: 10 AN: 10154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00426 AC: 287 AN: 67372

Other (OTH) AF: 0.00290 AC: 6 AN: 2072

Alfa AF: 0.00 Hom.: 277

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ASCL1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=171/29	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs3832799; hg19: chr12-103352171;