X-119565324-C-G

Variant names:

• chrX-119565324-C-G
• rs1243678722
• NM_022101.4:c.32G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022101.4(STEEP1):​c.32G>C​(p.Cys11Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000899 in 111,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 21)
• Consequence: STEEP1 NM_022101.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STEEP1	NM_022101.4	c.32G>C	p.Cys11Ser	missense_variant	Exon 1 of 7	ENST00000644802.2	NP_071384.1
STEEP1	NM_001170570.2	c.32G>C	p.Cys11Ser	missense_variant	Exon 1 of 6		NP_001164041.1
STEEP1	NM_001170569.1	c.-223G>C		5_prime_UTR_variant	Exon 1 of 7		NP_001164040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STEEP1	ENST00000644802.2	c.32G>C	p.Cys11Ser	missense_variant	Exon 1 of 7		NM_022101.4	ENSP00000494123.2

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111201 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33357

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111201 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33357

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;N
PROVEAN	Uncertain	-4.2	D;.
REVEL	Uncertain	0.37
Sift	Benign	0.048	D;.
Sift4G	Uncertain	0.016	D;.
Polyphen		0.85	.;P
Vest4		0.76
MutPred		0.56		Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);
MVP		0.78
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs1243678722; hg19: chrX-118699287;