Genetic Variant NM_003369.4:c.539T>C (chr11-75911985-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L180Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

UVRAG
NM_003369.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

Publications

0 publications found

Variant links:

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]

UVRAG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UVRAG	NM_003369.4	MANE Select	c.539T>C	p.Leu180Pro	missense	Exon 6 of 15	NP_003360.2
UVRAG	NM_001386671.1		c.539T>C	p.Leu180Pro	missense	Exon 6 of 16	NP_001373600.1
UVRAG	NM_001386672.1		c.377T>C	p.Leu126Pro	missense	Exon 5 of 14	NP_001373601.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UVRAG	ENST00000356136.8	TSL:1 MANE Select	c.539T>C	p.Leu180Pro	missense	Exon 6 of 15	ENSP00000348455.3	Q9P2Y5-1
UVRAG	ENST00000876952.1		c.539T>C	p.Leu180Pro	missense	Exon 6 of 16	ENSP00000547011.1
UVRAG	ENST00000969466.1		c.539T>C	p.Leu180Pro	missense	Exon 6 of 15	ENSP00000639525.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461214

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111694

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.028

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.79

MutPred

0.50

Loss of helix (P = 0.0068)

MVP

0.30

MPC

1.3

ClinPred

0.92

GERP RS

4.1

Varity_R

0.38

gMVP

0.79

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over