rs16959641

Variant names:

• chr16-58020195-C-G
• rs16959641
• NM_024598.4:c.748C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024598.4(USB1):​c.748C>G​(p.Gln250Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,614,084 control chromosomes in the GnomAD database, including 5,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (381 hom., cov: 31)
  • Exomes 𝑓: 0.077 (4785 hom.)
• Consequence: USB1 NM_024598.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.27
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021330416).
• BP6: Variant 16-58020195-C-G is Benign according to our data. Variant chr16-58020195-C-G is described in ClinVar as Benign. ClinVar VariationId is 403597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

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.748C>G	p.Gln250Glu	missense	Exon 7 of 7	NP_078874.2
	USB1	NM_001195302.2		c.694C>G	p.Gln232Glu	missense	Exon 6 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001330568.2		c.595C>G	p.Gln199Glu	missense	Exon 7 of 7	NP_001317497.1	H3BNM8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	ENST00000219281.8	TSL:1 MANE Select	c.748C>G	p.Gln250Glu	missense	Exon 7 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000561568.6	TSL:4	c.709C>G	p.Gln237Glu	missense	Exon 7 of 7	ENSP00000457322.2	H3BTT8
	USB1	ENST00000539737.6	TSL:2	c.694C>G	p.Gln232Glu	missense	Exon 6 of 6	ENSP00000446143.2	Q9BQ65-2

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8904 AN: 152124 Hom.: 380 Cov.: 31

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0809

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0690 AC: 17355 AN: 251428 AF XY: 0.0719

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.0949

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.0741

GnomAD4 exome AF: 0.0769 AC: 112366 AN: 1461842 Hom.: 4785 Cov.: 32 AF XY: 0.0775 AC XY: 56388 AN XY: 727216

African (AFR) AF: 0.0118 AC: 396 AN: 33480

American (AMR) AF: 0.0381 AC: 1703 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 2456 AN: 26134

East Asian (EAS) AF: 0.0736 AC: 2923 AN: 39694

South Asian (SAS) AF: 0.0833 AC: 7185 AN: 86256

European-Finnish (FIN) AF: 0.0419 AC: 2236 AN: 53418

Middle Eastern (MID) AF: 0.0791 AC: 456 AN: 5768

European-Non Finnish (NFE) AF: 0.0815 AC: 90579 AN: 1111978

Other (OTH) AF: 0.0734 AC: 4432 AN: 60392

GnomAD4 genome AF: 0.0584 AC: 8894 AN: 152242 Hom.: 381 Cov.: 31 AF XY: 0.0574 AC XY: 4273 AN XY: 74430

African (AFR) AF: 0.0149 AC: 617 AN: 41540

American (AMR) AF: 0.0566 AC: 865 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3470

East Asian (EAS) AF: 0.0947 AC: 490 AN: 5176

South Asian (SAS) AF: 0.0867 AC: 418 AN: 4824

European-Finnish (FIN) AF: 0.0378 AC: 401 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0809 AC: 5502 AN: 68006

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0806 Hom.: 403

Bravo AF: 0.0575

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0752 AC: 290

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.0698 AC: 8475

Asia WGS AF: 0.0610 AC: 211 AN: 3478

EpiCase AF: 0.0857

EpiControl AF: 0.0852

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Poikiloderma with neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.12
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.051	B
Vest4		0.092
MPC		0.25
ClinPred		0.021	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.55
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs16959641; hg19: chr16-58054099; COSMIC: COSV54683204; COSMIC: COSV54683204;