Genetic Variant NM_024598.4:c.11C>A (chr16-58001494-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024598.4(USB1):c.11C>A(p.Ala4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USB1
NM_024598.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00400

Publications

3 publications found

Variant links:

Genes affected

USB1 (HGNC:25792): (U6 snRNA biogenesis phosphodiesterase 1) This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

USB1 Gene-Disease associations (from GenCC):

poikiloderma with neutropenia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09517473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024598.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USB1	NM_024598.4	MANE Select	c.11C>A	p.Ala4Glu	missense	Exon 1 of 7	NP_078874.2
USB1	NM_001195302.2		c.11C>A	p.Ala4Glu	missense	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
USB1	NM_001204911.2		c.11C>A	p.Ala4Glu	missense	Exon 1 of 4	NP_001191840.1	Q9BQ65-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USB1	ENST00000219281.8	TSL:1 MANE Select	c.11C>A	p.Ala4Glu	missense	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
USB1	ENST00000539737.6	TSL:2	c.11C>A	p.Ala4Glu	missense	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2
USB1	ENST00000896281.1		c.11C>A	p.Ala4Glu	missense	Exon 1 of 6	ENSP00000566340.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1449944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720280

African (AFR)

AF:

0.00

AC:

AN:

33238

American (AMR)

AF:

0.00

AC:

AN:

43416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39116

South Asian (SAS)

AF:

0.00

AC:

AN:

84282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106976

Other (OTH)

AF:

0.00

AC:

AN:

59832

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.095

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

0.0040

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

REVEL

Benign

0.066

Sift

Benign

0.032

Sift4G

Benign

0.067

Polyphen

0.091

Vest4

0.16

MutPred

0.26

Gain of solvent accessibility (P = 0.0411)

MVP

0.12

MPC

0.54

ClinPred

0.72

GERP RS

1.8

PromoterAI

0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.54

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over