1-201115099-C-T

Position:

• chr1-201115099-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001270601.2(ASCL5):​c.274G>A​(p.Glu92Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,079,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ASCL5 NM_001270601.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.94

Genes affected

ASCL5 (HGNC:33169): (achaete-scute family bHLH transcription factor 5) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to be part of RNA polymerase II transcription regulator complex and chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201115099-C-T is Pathogenic according to our data. Variant chr1-201115099-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3358881.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASCL5	NM_001270601.2	c.274G>A	p.Glu92Lys	missense_variant	2/2	ENST00000449188.3	NP_001257530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASCL5	ENST00000449188.3	c.274G>A	p.Glu92Lys	missense_variant	2/2	3	NM_001270601.2	ENSP00000472681	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 3 AN: 1079490 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 509622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000326

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Teeth, odd shapes of Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University

-

The ASCL5 c.274G>A variant was identified in lobodontia patients with autosomal dominant inheritance. This variant was segregated with the affected and not in the unaffected individuals from 6 unrelated families, suggesting the complete penetrance of the variant. It was absent in all the allele frequency databases and predicted to be damaging by various in silico prediction tools. In summary, it is classified as pathogenic based on ACMG guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Benign	0.95
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.71	D;D
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.56
MVP		0.82
GERP RS		4.7
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201084227;