Genetic Variant USB1:p.Ala3Glu (chr16-58001491-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.8C>A(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A3T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USB1
NM_024598.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.676

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
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=0.12297496).

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.8C>A	p.Ala3Glu	missense	Exon 1 of 7	NP_078874.2
USB1	NM_001195302.2		c.8C>A	p.Ala3Glu	missense	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
USB1	NM_001204911.2		c.8C>A	p.Ala3Glu	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.8C>A	p.Ala3Glu	missense	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
USB1	ENST00000539737.6	TSL:2	c.8C>A	p.Ala3Glu	missense	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2
USB1	ENST00000896281.1		c.8C>A	p.Ala3Glu	missense	Exon 1 of 6	ENSP00000566340.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33208

American (AMR)

AF:

0.00

AC:

AN:

43276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25920

East Asian (EAS)

AF:

0.00

AC:

AN:

39060

South Asian (SAS)

AF:

0.00

AC:

AN:

84124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51370

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106560

Other (OTH)

AF:

0.00

AC:

AN:

59782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

0.18

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.82

M_CAP

Benign

0.053

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

0.68

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.5

REVEL

Benign

0.16

Sift

Uncertain

0.016

Sift4G

Benign

0.084

Polyphen

0.88

Vest4

0.13

MutPred

0.17

Gain of solvent accessibility (P = 0.0145)

MVP

0.26

MPC

0.28

ClinPred

0.95

GERP RS

4.0

PromoterAI

-0.095

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.40

gMVP

0.69

Mutation Taster

=89/11

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over