Genetic Variant UFD1:c.-278A>G (chr22-19479363-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005659.7(UFD1):c.-278A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,224,780 control chromosomes in the GnomAD database, including 172,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20837 hom., cov: 33)

Exomes 𝑓: 0.53 ( 152152 hom. )

Consequence

UFD1
NM_005659.7 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.26

Variant links:

Genes affected

UFD1 (HGNC:12520): (ubiquitin recognition factor in ER associated degradation 1) The protein encoded by this gene forms a complex with two other proteins, nuclear protein localization-4 and valosin-containing protein, and this complex is necessary for the degradation of ubiquitinated proteins. In addition, this complex controls the disassembly of the mitotic spindle and the formation of a closed nuclear envelope after mitosis. Mutations in this gene have been associated with Catch 22 syndrome as well as cardiac and craniofacial defects. Alternative splicing results in multiple transcript variants encoding different isoforms. A related pseudogene has been identified on chromosome 18. [provided by RefSeq, Jun 2009]

UFD1 links:

CDC45 (HGNC:1739): (cell division cycle 45) The protein encoded by this gene was identified by its strong similarity with Saccharomyces cerevisiae Cdc45, an essential protein required to the initiation of DNA replication. Cdc45 is a member of the highly conserved multiprotein complex including Cdc6/Cdc18, the minichromosome maintenance proteins (MCMs) and DNA polymerase, which is important for early steps of DNA replication in eukaryotes. This protein has been shown to interact with MCM7 and DNA polymerase alpha. Studies of the similar gene in Xenopus suggested that this protein play a pivotal role in the loading of DNA polymerase alpha onto chromatin. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

CDC45 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 22-19479363-T-C is Benign according to our data. Variant chr22-19479363-T-C is described in ClinVar as [Benign]. Clinvar id is 1182312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UFD1	NM_005659.7 link	c.-278A>G		upstream_gene_variant		ENST00000263202.15	NP_005650.2	Q92890-2Q541A5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UFD1	ENST00000263202.15 link	c.-278A>G		upstream_gene_variant		1	NM_005659.7	ENSP00000263202.9		Q92890-2

Frequencies

GnomAD3 genomes

AF:

0.521

AC:

79229

AN:

151966

Hom.:

20815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.545

Gnomad AMR

AF:

0.511

Gnomad ASJ

AF:

0.622

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.604

Gnomad FIN

AF:

0.480

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.536

Gnomad OTH

AF:

0.535

GnomAD4 exome

AF:

0.529

AC:

567521

AN:

1072696

Hom.:

152152

Cov.:

AF XY:

0.531

AC XY:

282868

AN XY:

532464

show subpopulations

Gnomad4 AFR exome

AF:

0.505

Gnomad4 AMR exome

AF:

0.490

Gnomad4 ASJ exome

AF:

0.609

Gnomad4 EAS exome

AF:

0.346

Gnomad4 SAS exome

AF:

0.616

Gnomad4 FIN exome

AF:

0.492

Gnomad4 NFE exome

AF:

0.531

Gnomad4 OTH exome

AF:

0.541

GnomAD4 genome

AF:

0.521

AC:

79290

AN:

152084

Hom.:

20837

Cov.:

AF XY:

0.519

AC XY:

38556

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.511

Gnomad4 ASJ

AF:

0.622

Gnomad4 EAS

AF:

0.380

Gnomad4 SAS

AF:

0.605

Gnomad4 FIN

AF:

0.480

Gnomad4 NFE

AF:

0.536

Gnomad4 OTH

AF:

0.542

Alfa

AF:

0.488

Hom.:

4888

Bravo

AF:

0.517

Asia WGS

AF:

0.503

AC:

1749

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.28

DANN

Benign

0.52

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over