11-75912042-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_003369.4(UVRAG):c.593+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000969 in 1,600,228 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (11 hom.)
• Consequence: UVRAG NM_003369.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9013
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.96

Genes affected

UVRAG (HGNC:12640): (UV radiation resistance associated) This gene complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and encodes a protein with a C2 domain. The protein activates the Beclin1-PI(3)KC3 complex, promoting autophagy and suppressing the proliferation and tumorigenicity of human colon cancer cells. Chromosomal aberrations involving this gene are associated with left-right axis malformation and mutations in this gene have been associated with colon cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 11-75912042-A-G is Benign according to our data. Variant chr11-75912042-A-G is described in ClinVar as [Benign]. Clinvar id is 732984.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00494 (752/152304) while in subpopulation AFR AF= 0.0165 (687/41554). AF 95% confidence interval is 0.0155. There are 4 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 743 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UVRAG	NM_003369.4	c.593+3A>G		splice_donor_region_variant, intron_variant		ENST00000356136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UVRAG	ENST00000356136.8	c.593+3A>G		splice_donor_region_variant, intron_variant		1	NM_003369.4	P2
UVRAG	ENST00000528264.1	c.290+3A>G		splice_donor_region_variant, intron_variant		5
UVRAG	ENST00000528420.5	c.290+3A>G		splice_donor_region_variant, intron_variant		2		A1
UVRAG	ENST00000525872.1	n.61+3A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.000176

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00137 AC: 341 AN: 249662 Hom.: 4 AF XY: 0.00120 AC XY: 162 AN XY: 134922

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000935

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000551 AC: 798 AN: 1447924 Hom.: 11 Cov.: 26 AF XY: 0.000480 AC XY: 346 AN XY: 721096

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.000966

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00494 AC: 752 AN: 152304 Hom.: 4 Cov.: 32 AF XY: 0.00483 AC XY: 360 AN XY: 74482

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00240 Hom.: 1

Bravo AF: 0.00565

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.010		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: rs113183732; hg19: chr11-75623086;