16-58001528-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024598.4(USB1):c.45G>T(p.Glu15Asp) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USB1 NM_024598.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.272

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]

ACMG classification

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=0.12839782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USB1	NM_024598.4	c.45G>T	p.Glu15Asp	missense_variant	1/7	ENST00000219281.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USB1	ENST00000219281.8	c.45G>T	p.Glu15Asp	missense_variant	1/7	1	NM_024598.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0021	T;.;.;T
Eigen	Benign	0.054
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.21
MutPred		0.10		Gain of glycosylation at S12 (P = 0.1547);Gain of glycosylation at S12 (P = 0.1547);Gain of glycosylation at S12 (P = 0.1547);Gain of glycosylation at S12 (P = 0.1547);
MVP		0.30
MPC		0.53
ClinPred		0.93	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.085
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs2072558848; hg19: chr16-58035432;