rs3743559

Variant names:

• chr16-58001525-C-A
• rs3743559
• NM_024598.4:c.42C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-58001525-C-A
• chr16-58001525-C-G
• chr16-58001525-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.80
• Publications: 11 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

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.42C>A	p.Ser14Ser	synonymous	Exon 1 of 7	NP_078874.2
	USB1	NM_001195302.2		c.42C>A	p.Ser14Ser	synonymous	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001204911.2		c.42C>A	p.Ser14Ser	synonymous	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.42C>A	p.Ser14Ser	synonymous	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000539737.6	TSL:2	c.42C>A	p.Ser14Ser	synonymous	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2
	USB1	ENST00000896281.1		c.42C>A	p.Ser14Ser	synonymous	Exon 1 of 6	ENSP00000566340.1

Frequencies

GnomAD3 genomes AF: 0.0599 AC: 9106 AN: 152102 Hom.: 380 Cov.: 32

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

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.: 32 AF XY: 0.0773 AC XY: 55962 AN XY: 723850

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

GnomAD4 genome AF: 0.0598 AC: 9099 AN: 152220 Hom.: 381 Cov.: 32 AF XY: 0.0587 AC XY: 4367 AN XY: 74430

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: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0804 AC: 5467 AN: 67992

Other (OTH) AF: 0.0699 AC: 148 AN: 2116

Alfa AF: 0.0758 Hom.: 1112

Bravo AF: 0.0588

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.1
DANN	Benign	0.92
PhyloP100		-4.8
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743559; hg19: chr16-58035429; COSMIC: COSV54622308; COSMIC: COSV54622308;