22-19474943-C-G

Variant names:

• chr22-19474943-C-G
• rs5746744
• NM_005659.7:c.169+125G>C

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.169+125G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.845 in 992,450 control chromosomes in the GnomAD database, including 355,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58511 hom., cov: 29)
  • Exomes 𝑓: 0.84 (296586 hom.)
• Consequence: UFD1 NM_005659.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310
• Publications: 4 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-19474943-C-G is Benign according to our data. Variant chr22-19474943-C-G is described in ClinVar as Benign. ClinVar VariationId is 1255296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UFD1	NM_005659.7	c.169+125G>C		intron_variant	Intron 3 of 11	ENST00000263202.15	NP_005650.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UFD1	ENST00000263202.15	c.169+125G>C		intron_variant	Intron 3 of 11	1	NM_005659.7	ENSP00000263202.9

Frequencies

GnomAD3 genomes AF: 0.875 AC: 132981 AN: 151930 Hom.: 58453 Cov.: 29

Gnomad AFR AF: 0.962

Gnomad AMI AF: 0.835

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.924

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.869

GnomAD4 exome AF: 0.839 AC: 705236 AN: 840402 Hom.: 296586 AF XY: 0.842 AC XY: 362353 AN XY: 430466

African (AFR) AF: 0.966 AC: 18162 AN: 18792

American (AMR) AF: 0.886 AC: 22143 AN: 25004

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 14017 AN: 16426

East Asian (EAS) AF: 0.824 AC: 26805 AN: 32532

South Asian (SAS) AF: 0.922 AC: 46977 AN: 50954

European-Finnish (FIN) AF: 0.800 AC: 37044 AN: 46322

Middle Eastern (MID) AF: 0.921 AC: 2390 AN: 2596

European-Non Finnish (NFE) AF: 0.829 AC: 505910 AN: 610616

Other (OTH) AF: 0.855 AC: 31788 AN: 37160

GnomAD4 genome AF: 0.875 AC: 133100 AN: 152048 Hom.: 58511 Cov.: 29 AF XY: 0.875 AC XY: 65002 AN XY: 74318

African (AFR) AF: 0.962 AC: 39911 AN: 41490

American (AMR) AF: 0.881 AC: 13469 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2981 AN: 3470

East Asian (EAS) AF: 0.857 AC: 4410 AN: 5148

South Asian (SAS) AF: 0.925 AC: 4453 AN: 4816

European-Finnish (FIN) AF: 0.800 AC: 8453 AN: 10562

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56560 AN: 67972

Other (OTH) AF: 0.871 AC: 1834 AN: 2106

Alfa AF: 0.828 Hom.: 2973

Bravo AF: 0.882

Asia WGS AF: 0.894 AC: 3108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 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	-0.89
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		0.031
Mutation Taster		=100/0	polymorphism (auto)

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: rs5746744; hg19: chr22-19462466;