rs2291854

Positions:

• chr12-102959760-A-G
• chr12-102959760-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004316.4(ASCL1):​c.*446A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 152,252 control chromosomes in the GnomAD database, including 50,247 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50224 hom., cov: 32)
  • Exomes 𝑓: 0.90 (23 hom.)
• Consequence: ASCL1 NM_004316.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.136

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4	c.*446A>G		3_prime_UTR_variant	2/2	ENST00000266744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASCL1	ENST00000266744.4	c.*446A>G		3_prime_UTR_variant	2/2	1	NM_004316.4	P1

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123172 AN: 152076 Hom.: 50190 Cov.: 32

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.804

GnomAD4 exome AF: 0.897 AC: 52 AN: 58 Hom.: 23 Cov.: 0 AF XY: 0.889 AC XY: 32 AN XY: 36

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.875

GnomAD4 genome AF: 0.810 AC: 123255 AN: 152194 Hom.: 50224 Cov.: 32 AF XY: 0.814 AC XY: 60595 AN XY: 74406

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.871

Gnomad4 ASJ AF: 0.740

Gnomad4 EAS AF: 0.871

Gnomad4 SAS AF: 0.868

Gnomad4 FIN AF: 0.923

Gnomad4 NFE AF: 0.823

Gnomad4 OTH AF: 0.805

Alfa AF: 0.817 Hom.: 25881

Bravo AF: 0.800

Asia WGS AF: 0.857 AC: 2979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.71

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: rs2291854; hg19: chr12-103353538;