chrX-119560352-C-T

Variant names:

• chrX-119560352-C-T
• rs769335743
• NM_022101.4:c.158G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022101.4(STEEP1):​c.158G>A​(p.Arg53Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,095,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: STEEP1 NM_022101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.28
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31998056).

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.158G>A	p.Arg53Gln	missense	Exon 2 of 7	NP_071384.1	Q9H5V9-1
	STEEP1	NM_001170570.2		c.158G>A	p.Arg53Gln	missense	Exon 2 of 6	NP_001164041.1	Q9H5V9-3
	STEEP1	NM_001170569.1		c.11G>A	p.Arg4Gln	missense	Exon 2 of 7	NP_001164040.1	Q9H5V9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STEEP1	ENST00000644802.2	MANE Select	c.158G>A	p.Arg53Gln	missense	Exon 2 of 7	ENSP00000494123.2	Q9H5V9-1
	STEEP1	ENST00000868973.1		c.158G>A	p.Arg53Gln	missense	Exon 2 of 8	ENSP00000539032.1
	STEEP1	ENST00000536133.2	TSL:2	c.158G>A	p.Arg53Gln	missense	Exon 2 of 6	ENSP00000441786.1	Q9H5V9-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183051 AF XY: 0.0000148

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095642 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 1 AN XY: 361032

African (AFR) AF: 0.00 AC: 0 AN: 26349

American (AMR) AF: 0.00 AC: 0 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30189

South Asian (SAS) AF: 0.00 AC: 0 AN: 54031

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839883

Other (OTH) AF: 0.00 AC: 0 AN: 46004

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.000037	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.3
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.087	T
Sift4G	Benign	0.30	T
Polyphen		0.88	P
Vest4		0.41
MutPred		0.28		Loss of MoRF binding (P = 0.029)
MVP		0.42
ClinPred		0.63	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.89
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769335743; hg19: chrX-118694315;