rs769481947

Variant names:

• chr16-88713447-G-A
• rs769481947
• NM_001012759.3:c.873G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88713447-G-A
• chr16-88713447-G-C
• chr16-88713447-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001012759.3(CTU2):​c.873G>A​(p.Thr291Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,423,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CTU2 NM_001012759.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.444
• Publications: 5 publications found

Genes affected

CTU2 (HGNC:28005): (cytosolic thiouridylase subunit 2) This gene encodes a protein which is involved in the post-transcriptional modification of transfer RNAs (tRNAs). The encoded protein plays a role in thiolation of uridine residue present at the wobble position in a subset of tRNAs, resulting in enhanced codon reading accuracy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

CTU2 Gene-Disease associations (from GenCC):

• microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-88713447-G-A is Pathogenic according to our data. Variant chr16-88713447-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 585016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012759.3. 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
	CTU2	NM_001012759.3	MANE Select	c.873G>A	p.Thr291Thr	splice_region synonymous	Exon 8 of 15	NP_001012777.1	Q2VPK5-1
	CTU2	NM_001318507.2		c.1086G>A	p.Thr362Thr	splice_region synonymous	Exon 8 of 15	NP_001305436.1	H3BSW6
	CTU2	NM_001012762.3		c.873G>A	p.Thr291Thr	splice_region synonymous	Exon 8 of 14	NP_001012780.1	Q2VPK5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTU2	ENST00000453996.7	TSL:1 MANE Select	c.873G>A	p.Thr291Thr	splice_region synonymous	Exon 8 of 15	ENSP00000388320.2	Q2VPK5-1
	CTU2	ENST00000567949.5	TSL:1	c.1086G>A	p.Thr362Thr	splice_region synonymous	Exon 8 of 15	ENSP00000456908.1	H3BSW6
	CTU2	ENST00000564105.5	TSL:1	n.*584G>A		splice_region non_coding_transcript_exon	Exon 7 of 14	ENSP00000454923.1	H3BNM3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00000929 AC: 2 AN: 215286 AF XY: 0.00000848

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: 0.00000974

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1423670 Hom.: 0 Cov.: 37 AF XY: 0.00000565 AC XY: 4 AN XY: 707396

African (AFR) AF: 0.0000316 AC: 1 AN: 31648

American (AMR) AF: 0.00 AC: 0 AN: 33326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24228

East Asian (EAS) AF: 0.00 AC: 0 AN: 38910

South Asian (SAS) AF: 0.00 AC: 0 AN: 80898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50766

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5588

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1099682

Other (OTH) AF: 0.0000341 AC: 2 AN: 58624

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (5)
1	-	-	Microcephaly (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769481947; hg19: chr16-88779855; COSMIC: COSV56344093; COSMIC: COSV56344093;