chr16-58001433-G-C

Variant names:

• chr16-58001433-G-C
• rs73546949
• NM_024598.4:c.-51G>C

Variant summary

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

The NM_024598.4(USB1):​c.-51G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,556,442 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: USB1 NM_024598.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0220
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.75).
• BP6: Variant 16-58001433-G-C is Benign according to our data. Variant chr16-58001433-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1706801.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0048 (731/152324) while in subpopulation AFR AF = 0.0165 (688/41580). AF 95% confidence interval is 0.0155. There are 8 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.-51G>C		5_prime_UTR	Exon 1 of 7	NP_078874.2
	USB1	NM_001195302.2		c.-51G>C		5_prime_UTR	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001204911.2		c.-51G>C		5_prime_UTR	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.-51G>C		5_prime_UTR	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000561568.6	TSL:4	c.-97G>C		5_prime_UTR	Exon 1 of 7	ENSP00000457322.2	H3BTT8
	USB1	ENST00000539737.6	TSL:2	c.-51G>C		5_prime_UTR	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 710 AN: 152206 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00106 AC: 171 AN: 161838 AF XY: 0.00101

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000894

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000504 AC: 708 AN: 1404118 Hom.: 4 Cov.: 30 AF XY: 0.000453 AC XY: 314 AN XY: 693820

African (AFR) AF: 0.0168 AC: 536 AN: 31888

American (AMR) AF: 0.000952 AC: 35 AN: 36758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 36300

South Asian (SAS) AF: 0.0000501 AC: 4 AN: 79864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48682

Middle Eastern (MID) AF: 0.000762 AC: 4 AN: 5252

European-Non Finnish (NFE) AF: 0.0000508 AC: 55 AN: 1081914

Other (OTH) AF: 0.00127 AC: 74 AN: 58178

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152324 Hom.: 8 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74480

African (AFR) AF: 0.0165 AC: 688 AN: 41580

American (AMR) AF: 0.00189 AC: 29 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.00538

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.75
CADD	Benign	5.5
DANN	Benign	0.80
PhyloP100		-0.022
PromoterAI		-0.080	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs73546949; hg19: chr16-58035337;