16-58001503-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024598.4(USB1):c.20T>C(p.Val7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,605,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

USB1
NM_024598.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.419

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.100836694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USB1	NM_024598.4 linkuse as main transcript	c.20T>C	p.Val7Ala	missense_variant	1/7	ENST00000219281.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USB1	ENST00000219281.8 linkuse as main transcript	c.20T>C	p.Val7Ala	missense_variant	1/7	1	NM_024598.4		Q9BQ65-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000347

AC:

AN:

230530

Hom.:

AF XY:

0.0000397

AC XY:

AN XY:

125886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000522

Gnomad NFE exome

AF:

0.0000683

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000317

AC:

AN:

1453222

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

722198

show subpopulations

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:

0.0000387

Gnomad4 NFE exome

AF:

0.0000397

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74292

show subpopulations

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.20T>C (p.V7A) alteration is located in exon 1 (coding exon 1) of the USB1 gene. This alteration results from a T to C substitution at nucleotide position 20, causing the valine (V) at amino acid position 7 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 7 of the USB1 protein (p.Val7Ala). This variant is present in population databases (rs373657742, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with USB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 852007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USB1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.23

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.0097

T;.;.;T

Eigen

Benign

-0.024

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.092

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.55

P;.;.;.

Vest4

0.11

MVP

0.41

MPC

0.93

ClinPred

0.41

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.37

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over