chrX-119545508-C-T

Variant names:

• chrX-119545508-C-T
• NM_022101.4:c.243-4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022101.4(STEEP1):​c.243-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000959 in 1,042,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: STEEP1 NM_022101.4 splice_region, intron
• Scores: Splicing: ADA: 0.0009197
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.536
• Publications: 0 publications found

Genes affected

STEEP1 (HGNC:26239): (STING1 ER exit protein 1) While this gene is well-supported by transcript data, no functional information on its protein products is currently available. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

UBE2A (HGNC:12472): (ubiquitin conjugating enzyme E2 A) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is required for post-replicative DNA damage repair, and may play a role in transcriptional regulation. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

UBE2A Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Nascimento type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022101.4. 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
	STEEP1	NM_022101.4	MANE Select	c.243-4G>A		splice_region intron	N/A	NP_071384.1	Q9H5V9-1
	STEEP1	NM_001170570.2		c.243-1017G>A		intron	N/A	NP_001164041.1	Q9H5V9-3
	STEEP1	NM_001170569.1		c.96-4G>A		splice_region intron	N/A	NP_001164040.1	Q9H5V9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STEEP1	ENST00000644802.2	MANE Select	c.243-4G>A		splice_region intron	N/A	ENSP00000494123.2	Q9H5V9-1
	UBE2A	ENST00000696533.1		c.-157-28135C>T		intron	N/A	ENSP00000512694.1	A0A8Q3SIL6
	UBE2A	ENST00000696539.1		c.-376+2857C>T		intron	N/A	ENSP00000512700.1	A0A8Q3SIL6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.59e-7 AC: 1 AN: 1042726 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 316598

African (AFR) AF: 0.00 AC: 0 AN: 25312

American (AMR) AF: 0.00 AC: 0 AN: 34893

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18910

East Asian (EAS) AF: 0.00 AC: 0 AN: 29651

South Asian (SAS) AF: 0.00 AC: 0 AN: 52920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39895

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3966

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 793064

Other (OTH) AF: 0.00 AC: 0 AN: 44115

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.5
DANN	Benign	0.76
PhyloP100		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.028
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: chrX-118679471;