dbSNP rs187814735: STEEP1:p.Arg55Leu (chrX-119560346-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022101.4(STEEP1):c.164G>T(p.Arg55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,998 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. 12/19 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. R55Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

STEEP1
NM_022101.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.23

Publications

0 publications found

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 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)

UBE2A links:

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ACMG classification

Classification was made for transcript

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=0.30320185).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STEEP1	NM_022101.4	MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 2 of 7	NP_071384.1	Q9H5V9-1
STEEP1	NM_001170570.2		c.164G>T	p.Arg55Leu	missense	Exon 2 of 6	NP_001164041.1	Q9H5V9-3
STEEP1	NM_001170569.1		c.17G>T	p.Arg6Leu	missense	Exon 2 of 7	NP_001164040.1	Q9H5V9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STEEP1	ENST00000644802.2	MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 2 of 7	ENSP00000494123.2	Q9H5V9-1
STEEP1	ENST00000868973.1		c.164G>T	p.Arg55Leu	missense	Exon 2 of 8	ENSP00000539032.1
STEEP1	ENST00000536133.2	TSL:2	c.164G>T	p.Arg55Leu	missense	Exon 2 of 6	ENSP00000441786.1	Q9H5V9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094998

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26336

American (AMR)

AF:

0.00

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.00

AC:

AN:

54037

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839294

Other (OTH)

AF:

0.00

AC:

AN:

45985

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.014

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.5

PhyloP100

2.2

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.12

Sift

Benign

0.038

Sift4G

Uncertain

0.052

Polyphen

0.16

Vest4

0.43

MutPred

0.35

Loss of disorder (P = 0.0276)

MVP

0.18

ClinPred

0.85

GERP RS

4.7

Varity_R

0.27

gMVP

0.95

Mutation Taster

=76/24

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over