rs1335865347

Variant names:

• chr16-58001530-A-G
• rs1335865347
• NM_024598.4:c.47A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-58001530-A-G
• chr16-58001530-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024598.4(USB1):​c.47A>G​(p.Asp16Gly) 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. 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: 0.496
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	NM_024598.4	MANE Select	c.47A>G	p.Asp16Gly	missense	Exon 1 of 7	NP_078874.2
	USB1	NM_001195302.2		c.47A>G	p.Asp16Gly	missense	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001204911.2		c.47A>G	p.Asp16Gly	missense	Exon 1 of 4	NP_001191840.1	Q9BQ65-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	ENST00000219281.8	TSL:1 MANE Select	c.47A>G	p.Asp16Gly	missense	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000561568.6	TSL:4	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000457322.2	H3BTT8
	USB1	ENST00000539737.6	TSL:2	c.47A>G	p.Asp16Gly	missense	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	33
DANN	Benign	0.93
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.50
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.13
Sift	Uncertain	0.014	D
Sift4G	Benign	0.091	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.28
MPC		0.84
ClinPred		0.95	D
GERP RS		1.3
PromoterAI		0.29	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.22
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1335865347; hg19: chr16-58035434;