chr1-154236580-C-T

Variant names:

• chr1-154236580-C-T
• NM_014847.4:c.559C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014847.4(UBAP2L):​c.559C>T​(p.Arg187*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBAP2L NM_014847.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.749
• Publications: 0 publications found

Genes affected

UBAP2L (HGNC:29877): (ubiquitin associated protein 2 like) Enables RNA binding activity. Involved in binding activity of sperm to zona pellucida and stress granule assembly. Acts upstream of or within hematopoietic stem cell homeostasis. Part of PcG protein complex. [provided by Alliance of Genome Resources, Apr 2022]

UBAP2L Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-154236580-C-T is Pathogenic according to our data. Variant chr1-154236580-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3639923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014847.4. 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
	UBAP2L	NM_014847.4	MANE Select	c.559C>T	p.Arg187*	stop_gained	Exon 7 of 27	NP_055662.3
	UBAP2L	NM_001375612.1		c.592C>T	p.Arg198*	stop_gained	Exon 7 of 28	NP_001362541.1
	UBAP2L	NM_001375614.1		c.559C>T	p.Arg187*	stop_gained	Exon 7 of 28	NP_001362543.1	Q14157-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBAP2L	ENST00000428931.6	TSL:5 MANE Select	c.559C>T	p.Arg187*	stop_gained	Exon 7 of 27	ENSP00000389445.1	Q14157-2
	UBAP2L	ENST00000361546.6	TSL:1	c.559C>T	p.Arg187*	stop_gained	Exon 6 of 26	ENSP00000355343.2	Q14157-2
	UBAP2L	ENST00000343815.10	TSL:1	c.559C>T	p.Arg187*	stop_gained	Exon 7 of 25	ENSP00000345308.6	Q14157-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		0.75
Vest4		0.49
GERP RS		2.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=10/190	disease causing (fs/PTC)

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

hg19: chr1-154209056;