12-102958048-T-C

Position:

• chr12-102958048-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004316.4(ASCL1):​c.-197T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 407,558 control chromosomes in the GnomAD database, including 22,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10284 hom., cov: 32)
  • Exomes 𝑓: 0.30 (12301 hom.)
• Consequence: ASCL1 NM_004316.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.365

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-102958048-T-C is Benign according to our data. Variant chr12-102958048-T-C is described in ClinVar as [Benign]. Clinvar id is 1229581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.-197T>C		5_prime_UTR_variant	1/2	ENST00000266744.4
PAH	NM_001354304.2	c.-96+147A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.-197T>C		5_prime_UTR_variant	1/2	1	NM_004316.4	P1
PAH	ENST00000551337.5	c.-96+147A>G		intron_variant		3
PAH	ENST00000547319.1	n.216+147A>G		intron_variant, non_coding_transcript_variant		4
PAH	ENST00000635500.1	n.28+147A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53834 AN: 151796 Hom.: 10275 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.301 AC: 76964 AN: 255646 Hom.: 12301 Cov.: 4 AF XY: 0.300 AC XY: 38962 AN XY: 130024

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.355 AC: 53870 AN: 151912 Hom.: 10284 Cov.: 32 AF XY: 0.349 AC XY: 25912 AN XY: 74274

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.340

Alfa AF: 0.317 Hom.: 16085

Bravo AF: 0.361

Asia WGS AF: 0.201 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.68

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: rs9782; hg19: chr12-103351826;