16-58001305-T-G

Variant names:

• chr16-58001305-T-G
• rs76764258
• ENST00000698445.1:c.-179T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001330568.2(USB1):​c.-55-1174T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 730,338 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: USB1 NM_001330568.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.735
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-58001305-T-G is Benign according to our data. Variant chr16-58001305-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1706949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00911 (1387/152206) while in subpopulation AFR AF = 0.0314 (1305/41550). AF 95% confidence interval is 0.03. There are 28 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330568.2. 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_001330568.2		c.-55-1174T>G		intron	N/A	NP_001317497.1	H3BNM8
	USB1	NM_024598.4	MANE Select	c.-179T>G		upstream_gene	N/A	NP_078874.2
	USB1	NM_001195302.2		c.-179T>G		upstream_gene	N/A	NP_001182231.1	Q9BQ65-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	ENST00000698445.1		c.-179T>G		5_prime_UTR	Exon 1 of 6	ENSP00000513727.1	A0A8V8TM89
	USB1	ENST00000561743.5	TSL:3	c.-55-1174T>G		intron	N/A	ENSP00000454928.1	H3BNM8
	USB1	ENST00000698444.1		c.-55-1174T>G		intron	N/A	ENSP00000513726.1	H3BNM8

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1384 AN: 152088 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00110 AC: 636 AN: 578132 Hom.: 8 AF XY: 0.000877 AC XY: 268 AN XY: 305666

African (AFR) AF: 0.0307 AC: 485 AN: 15818

American (AMR) AF: 0.00184 AC: 53 AN: 28758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17442

East Asian (EAS) AF: 0.00 AC: 0 AN: 31814

South Asian (SAS) AF: 0.000106 AC: 6 AN: 56584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32246

Middle Eastern (MID) AF: 0.00127 AC: 3 AN: 2358

European-Non Finnish (NFE) AF: 0.0000386 AC: 14 AN: 362344

Other (OTH) AF: 0.00244 AC: 75 AN: 30768

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152206 Hom.: 28 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74412

African (AFR) AF: 0.0314 AC: 1305 AN: 41550

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67980

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00789 Hom.: 1

Bravo AF: 0.0104

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.7
DANN	Benign	0.41
PhyloP100		-0.73
PromoterAI		-0.045	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs76764258; hg19: chr16-58035209;