16-58001541-G-T

Variant names:

• chr16-58001541-G-T
• rs1227473466
• NM_024598.4:c.58G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024598.4(USB1):​c.58G>T​(p.Asp20Tyr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USB1 NM_024598.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.637

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USB1	NM_024598.4	c.58G>T	p.Asp20Tyr	missense_variant	Exon 1 of 7	ENST00000219281.8	NP_078874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8	c.58G>T	p.Asp20Tyr	missense_variant	Exon 1 of 7	1	NM_024598.4	ENSP00000219281.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.010	T;.;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.041	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.044	B;.;.;.
Vest4		0.20
MutPred		0.13		Gain of phosphorylation at D20 (P = 0.0047);Gain of phosphorylation at D20 (P = 0.0047);Gain of phosphorylation at D20 (P = 0.0047);Gain of phosphorylation at D20 (P = 0.0047);
MVP		0.13
MPC		0.33
ClinPred		0.11	T
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.088
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1227473466; hg19: chr16-58035445;