22-19479363-T-C

Variant names:

• chr22-19479363-T-C
• rs5992403
• NM_005659.7:c.-278A>G

Variant summary

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

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 16 publications found

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]

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 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  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 (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 VariationId 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	c.-278A>G		upstream_gene_variant		ENST00000263202.15	NP_005650.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79229 AN: 151966 Hom.: 20815 Cov.: 33

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.: 14 AF XY: 0.531 AC XY: 282868 AN XY: 532464

African (AFR) AF: 0.505 AC: 12067 AN: 23898

American (AMR) AF: 0.490 AC: 11471 AN: 23420

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 11057 AN: 18160

East Asian (EAS) AF: 0.346 AC: 11377 AN: 32886

South Asian (SAS) AF: 0.616 AC: 38176 AN: 62008

European-Finnish (FIN) AF: 0.492 AC: 21328 AN: 43344

Middle Eastern (MID) AF: 0.585 AC: 2468 AN: 4216

European-Non Finnish (NFE) AF: 0.531 AC: 434627 AN: 818656

Other (OTH) AF: 0.541 AC: 24950 AN: 46108

GnomAD4 genome AF: 0.521 AC: 79290 AN: 152084 Hom.: 20837 Cov.: 33 AF XY: 0.519 AC XY: 38556 AN XY: 74328

African (AFR) AF: 0.510 AC: 21151 AN: 41470

American (AMR) AF: 0.511 AC: 7812 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1964 AN: 5162

South Asian (SAS) AF: 0.605 AC: 2915 AN: 4822

European-Finnish (FIN) AF: 0.480 AC: 5081 AN: 10584

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36402 AN: 67962

Other (OTH) AF: 0.542 AC: 1144 AN: 2112

Alfa AF: 0.499 Hom.: 6662

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

Submissions by phenotype

not provided Benign:2

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.28
DANN	Benign	0.52
PhyloP100		-1.3
PromoterAI		-0.050	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: rs5992403; hg19: chr22-19466886; COSMIC: COSV54248497;