1-201115099-C-T

Variant names:

• chr1-201115099-C-T
• rs1663310866
• NM_001270601.2:c.274G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 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 VariationId is 3358881.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270601.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL5	NM_001270601.2	MANE Select	c.274G>A	p.Glu92Lys	missense	Exon 2 of 2	NP_001257530.1	M0R2M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL5	ENST00000449188.3	TSL:3 MANE Select	c.274G>A	p.Glu92Lys	missense	Exon 2 of 2	ENSP00000472681.1	M0R2M9

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

African (AFR) AF: 0.00 AC: 0 AN: 22960

American (AMR) AF: 0.00 AC: 0 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14384

East Asian (EAS) AF: 0.00 AC: 0 AN: 26518

South Asian (SAS) AF: 0.00 AC: 0 AN: 19488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2916

European-Non Finnish (NFE) AF: 0.00000326 AC: 3 AN: 920034

Other (OTH) AF: 0.00 AC: 0 AN: 43668

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Teeth, odd shapes of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
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
PhyloP100		5.9
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D
Vest4		0.56
MVP		0.82
GERP RS		4.7
gMVP		0.64
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1663310866; hg19: chr1-201084227;