11-93730101-C-T

Variant names:

• chr11-93730101-C-T
• rs1048439804
• NM_033395.2:c.7720C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_033395.2(CEP295):​c.7720C>T​(p.Gln2574*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,398,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CEP295 NM_033395.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

Genes affected

CEP295 (HGNC:29366): (centrosomal protein 295) Enables microtubule binding activity. Involved in several processes, including centriole replication; positive regulation of protein acetylation; and regulation of centrosome duplication. Located in cytosol; microtubule cytoskeleton; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TAF1D (HGNC:28759): (TATA-box binding protein associated factor, RNA polymerase I subunit D) TAF1D is a member of the SL1 complex, which includes TBP (MIM 600075) and TAF1A (MIM 604903), TAF1B (MIM 604904), and TAF1C (MIM 604905), and plays a role in RNA polymerase I transcription (Wang et al., 2004 [PubMed 15520167]; Gorski et al., 2007 [PubMed 17318177]).[supplied by OMIM, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.011 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033395.2. 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
	CEP295	NM_033395.2	MANE Select	c.7720C>T	p.Gln2574*	stop_gained	Exon 29 of 30	NP_203753.1	Q9C0D2-1
	TAF1D	NR_146090.2		n.*93G>A		downstream_gene	N/A
	TAF1D	NR_146091.2		n.*93G>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP295	ENST00000325212.11	TSL:2 MANE Select	c.7720C>T	p.Gln2574*	stop_gained	Exon 29 of 30	ENSP00000316681.6	Q9C0D2-1
	CEP295	ENST00000531700.5	TSL:2	c.2260C>T	p.Gln754*	stop_gained	Exon 16 of 17	ENSP00000437323.1	Q9C0D2-2
	TAF1D	ENST00000323981.6	TSL:2	n.*1350G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000314971.2	Q9H5J8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000641 AC: 1 AN: 155946 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1398912 Hom.: 0 Cov.: 34 AF XY: 0.00000580 AC XY: 4 AN XY: 689964

African (AFR) AF: 0.00 AC: 0 AN: 31552

American (AMR) AF: 0.00 AC: 0 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35672

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078784

Other (OTH) AF: 0.00 AC: 0 AN: 57986

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.60	D
PhyloP100		1.8
Vest4		0.19
GERP RS		2.6
Mutation Taster		=49/151	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1048439804; hg19: chr11-93463267;