NM_024598.4:c.42C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_024598.4(USB1):c.42C>A(p.Ser14Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,608,316 control chromosomes in the GnomAD database, including 5,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 381 hom., cov: 32)

Exomes 𝑓: 0.077 ( 4708 hom. )

Consequence

USB1
NM_024598.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.80

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 16-58001525-C-A is Benign according to our data. Variant chr16-58001525-C-A is described in ClinVar as Benign. ClinVar VariationId is 403596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USB1	NM_024598.4 link	c.42C>A	p.Ser14Ser	synonymous_variant	Exon 1 of 7	ENST00000219281.8	NP_078874.2	Q9BQ65-1A0A024R6V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8 link	c.42C>A	p.Ser14Ser	synonymous_variant	Exon 1 of 7	1	NM_024598.4	ENSP00000219281.3		Q9BQ65-1

Frequencies

GnomAD3 genomes

AF:

0.0599

AC:

9106

AN:

152102

Hom.:

380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.0569

Gnomad ASJ

AF:

0.0945

Gnomad EAS

AF:

0.0942

Gnomad SAS

AF:

0.0882

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.0702

GnomAD2 exomes

AF:

0.0697

AC:

16339

AN:

234572

AF XY:

0.0723

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.0350

Gnomad ASJ exome

AF:

0.0943

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0819

Gnomad OTH exome

AF:

0.0743

GnomAD4 exome

AF:

0.0767

AC:

111628

AN:

1456096

Hom.:

4708

Cov.:

AF XY:

0.0773

AC XY:

55962

AN XY:

723850

show subpopulations

African (AFR)

AF:

0.0173

AC:

576

AN:

33374

American (AMR)

AF:

0.0381

AC:

1683

AN:

44228

Ashkenazi Jewish (ASJ)

AF:

0.0940

AC:

2446

AN:

26034

East Asian (EAS)

AF:

0.0736

AC:

2903

AN:

39458

South Asian (SAS)

AF:

0.0834

AC:

7118

AN:

85326

European-Finnish (FIN)

AF:

0.0420

AC:

2183

AN:

52000

Middle Eastern (MID)

AF:

0.0798

AC:

459

AN:

5752

European-Non Finnish (NFE)

AF:

0.0809

AC:

89840

AN:

1109838

Other (OTH)

AF:

0.0736

AC:

4420

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6928

13856

20783

27711

34639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3292

6584

9876

13168

16460

<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

AF:

0.0598

AC:

9099

AN:

152220

Hom.:

381

Cov.:

AF XY:

0.0587

AC XY:

4367

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0207

AC:

858

AN:

41528

American (AMR)

AF:

0.0568

AC:

869

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0945

AC:

328

AN:

3472

East Asian (EAS)

AF:

0.0937

AC:

484

AN:

5166

South Asian (SAS)

AF:

0.0875

AC:

422

AN:

4824

European-Finnish (FIN)

AF:

0.0377

AC:

400

AN:

10610

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0804

AC:

5467

AN:

67992

Other (OTH)

AF:

0.0699

AC:

148

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

437

874

1312

1749

2186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0758

Hom.:

1112

Bravo

AF:

0.0588

Asia WGS

AF:

0.0630

AC:

218

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Poikiloderma with neutropenia

Benign:1

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.1

(source)

DANN

Benign

0.92

PhyloP100

-4.8

PromoterAI

-0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over