chr22-19450821-G-A

Position:

• chr22-19450821-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005659.7(UFD1):​c.850-77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,606,858 control chromosomes in the GnomAD database, including 3,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1825 hom., cov: 31)
  • Exomes 𝑓: 0.0090 (1638 hom.)
• Consequence: UFD1 NM_005659.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.938

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-19450821-G-A is Benign according to our data. Variant chr22-19450821-G-A is described in ClinVar as [Benign]. Clinvar id is 1236720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UFD1	NM_005659.7	c.850-77C>T		intron_variant		ENST00000263202.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UFD1	ENST00000263202.15	c.850-77C>T		intron_variant		1	NM_005659.7	P1
UFD1	ENST00000399523.5	c.797-77C>T		intron_variant		1
UFD1	ENST00000459854.5	n.4838C>T		non_coding_transcript_exon_variant	11/11	1
UFD1	ENST00000466373.1	n.2940-77C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 12951 AN: 151908 Hom.: 1822 Cov.: 31

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0665

GnomAD4 exome AF: 0.00895 AC: 13028 AN: 1454832 Hom.: 1638 Cov.: 30 AF XY: 0.00773 AC XY: 5592 AN XY: 723162

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000628

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000628

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0853 AC: 12974 AN: 152026 Hom.: 1825 Cov.: 31 AF XY: 0.0821 AC XY: 6105 AN XY: 74340

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0815 Hom.: 301

Bravo AF: 0.0971

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs8137166; hg19: chr22-19438344;