1-162522504-C-T

Variant names:

• chr1-162522504-C-T
• rs869312863
• NM_175866.5:c.1214C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The ENST00000489294.2(UHMK1):​c.1214C>T​(p.Pro405Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UHMK1 ENST00000489294.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.92
• Publications: 4 publications found

Genes affected

UHMK1 (HGNC:19683): (U2AF homology motif kinase 1) The gene encodes a serine/threonine protein kinase that promotes cell cycle progression through G1 by phosphorylation of the cyclin-dependent kinase inhibitor 1B (p27Kip1), which causes nuclear export and degradation. The encoded protein is also thought to function in the adult nervous system and the gene has been associated with schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.84423 (below the threshold of 3.09). Trascript score misZ: 1.1318 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753
• PP5: Variant 1-162522504-C-T is Pathogenic according to our data. Variant chr1-162522504-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 224812.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000489294.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UHMK1	NM_175866.5	MANE Select	c.1214C>T	p.Pro405Leu	missense	Exon 8 of 8	NP_787062.1
	UHMK1	NM_001184763.1		c.992C>T	p.Pro331Leu	missense	Exon 8 of 8	NP_001171692.1
	UHMK1	NM_144624.2		c.*90C>T		3_prime_UTR	Exon 7 of 7	NP_653225.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UHMK1	ENST00000489294.2	TSL:1 MANE Select	c.1214C>T	p.Pro405Leu	missense	Exon 8 of 8	ENSP00000420270.1
	UHMK1	ENST00000538489.5	TSL:1	c.*90C>T		3_prime_UTR	Exon 7 of 7	ENSP00000446416.1
	UHMK1	ENST00000545294.5	TSL:2	c.992C>T	p.Pro331Leu	missense	Exon 8 of 8	ENSP00000441226.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251354 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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral visual impairment and intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.47		Loss of glycosylation at T402 (P = 0.044)
MVP		0.76
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.79
Mutation Taster		=39/61	disease causing (ClinVar)

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: rs869312863; hg19: chr1-162492294; COSMIC: COSV56421423;