Genetic Variant NM_022101.4:c.355G>A (chrX-119544421-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022101.4(STEEP1):c.355G>A(p.Val119Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

STEEP1
NM_022101.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20

Variant links:

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]

STEEP1 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28822997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STEEP1	NM_022101.4 link	c.355G>A	p.Val119Ile	missense_variant	Exon 4 of 7	ENST00000644802.2	NP_071384.1	Q9H5V9-1
STEEP1	NM_001170570.2 link	c.313G>A	p.Val105Ile	missense_variant	Exon 3 of 6		NP_001164041.1	Q9H5V9-3
STEEP1	NM_001170569.1 link	c.208G>A	p.Val70Ile	missense_variant	Exon 4 of 7		NP_001164040.1	Q9H5V9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STEEP1	ENST00000644802.2 link	c.355G>A	p.Val119Ile	missense_variant	Exon 4 of 7		NM_022101.4	ENSP00000494123.2		Q9H5V9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1094252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359690

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 14, 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 does not alter 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

Benign

0.094

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0060

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;L

PROVEAN

Benign

0.38

N;N;.

REVEL

Benign

0.028

Sift

Benign

0.10

T;T;.

Sift4G

Benign

0.40

T;T;.

Polyphen

0.0040

.;.;B

Vest4

0.36

MutPred

0.47

.;.;Loss of sheet (P = 0.0315);

MVP

0.27

ClinPred

0.53

GERP RS

4.8

Varity_R

0.11

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over