X-119544489-C-T

Position:

• chrX-119544489-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022101.4(STEEP1):​c.287G>A​(p.Cys96Tyr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 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)
• Consequence: STEEP1 NM_022101.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STEEP1	NM_022101.4	c.287G>A	p.Cys96Tyr	missense_variant, splice_region_variant	4/7	ENST00000644802.2	NP_071384.1
STEEP1	NM_001170570.2	c.245G>A	p.Cys82Tyr	missense_variant, splice_region_variant	3/6		NP_001164041.1
STEEP1	NM_001170569.1	c.140G>A	p.Cys47Tyr	missense_variant, splice_region_variant	4/7		NP_001164040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STEEP1	ENST00000644802.2	c.287G>A	p.Cys96Tyr	missense_variant, splice_region_variant	4/7		NM_022101.4	ENSP00000494123.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 107 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Dec 21, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked intellectual developmental disorder 107 (MIM#301013). (I) 0109 - This gene is associated with X-linked recessive disease. Carrier females may be asymptomatic due to skewed X-inactivation or mildly affected (PMID: 29374277, 31822863). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;T;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	.;.;M
PROVEAN	Pathogenic	-10	D;D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	.;.;D
Vest4		0.96
MutPred		0.77		.;.;Loss of methylation at K95 (P = 0.0245);
MVP		0.91
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-118678452;