1-154225082-A-T

Variant names:

• chr1-154225082-A-T
• rs112188834
• ENST00000361546.6:c.-42A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014847.4(UBAP2L):​c.-40-2A>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBAP2L NM_014847.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• 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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.-40-2A>T		splice_acceptor intron	N/A	NP_055662.3
	UBAP2L	NM_001375612.1		c.-40-2A>T		splice_acceptor intron	N/A	NP_001362541.1
	UBAP2L	NM_001375614.1		c.-40-2A>T		splice_acceptor intron	N/A	NP_001362543.1	Q14157-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBAP2L	ENST00000361546.6	TSL:1	c.-42A>T		5_prime_UTR	Exon 1 of 26	ENSP00000355343.2	Q14157-2
	UBAP2L	ENST00000428931.6	TSL:5 MANE Select	c.-40-2A>T		splice_acceptor intron	N/A	ENSP00000389445.1	Q14157-2
	UBAP2L	ENST00000343815.10	TSL:1	c.-40-2A>T		splice_acceptor intron	N/A	ENSP00000345308.6	Q14157-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Benign	0.97
PhyloP100		6.8
PromoterAI		-0.0010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.77		Position offset: 2

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

Other links and lift over

dbSNP: rs112188834; hg19: chr1-154197558;