11-75911985-T-C

Variant names:

• chr11-75911985-T-C
• rs756312250
• NM_003369.4:c.539T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003369.4(UVRAG):​c.539T>C​(p.Leu180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UVRAG NM_003369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UVRAG	NM_003369.4	c.539T>C	p.Leu180Pro	missense_variant	Exon 6 of 15	ENST00000356136.8	NP_003360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UVRAG	ENST00000356136.8	c.539T>C	p.Leu180Pro	missense_variant	Exon 6 of 15	1	NM_003369.4	ENSP00000348455.3
UVRAG	ENST00000528420.5	c.236T>C	p.Leu79Pro	missense_variant	Exon 6 of 15	2		ENSP00000436039.1
UVRAG	ENST00000528264.1	c.236T>C	p.Leu79Pro	missense_variant	Exon 4 of 5	5		ENSP00000433613.1
UVRAG	ENST00000525872.1	n.7T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461214 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539T>C (p.L180P) alteration is located in exon 6 (coding exon 6) of the UVRAG gene. This alteration results from a T to C substitution at nucleotide position 539, causing the leucine (L) at amino acid position 180 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;N;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.50		Loss of helix (P = 0.0068);.;.;
MVP		0.30
MPC		1.3
ClinPred		0.92	D
GERP RS		4.1
Varity_R		0.38
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs756312250; hg19: chr11-75623029;