11-75879994-T-C

Variant names:

• chr11-75879994-T-C
• rs1259395722
• NM_003369.4:c.386T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003369.4(UVRAG):​c.386T>C​(p.Ile129Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,862 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: 0.0000055 (0 hom.)
• Consequence: UVRAG NM_003369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UVRAG	NM_003369.4	c.386T>C	p.Ile129Thr	missense_variant	Exon 4 of 15	ENST00000356136.8	NP_003360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UVRAG	ENST00000356136.8	c.386T>C	p.Ile129Thr	missense_variant	Exon 4 of 15	1	NM_003369.4	ENSP00000348455.3
UVRAG	ENST00000528420.5	c.83T>C	p.Ile28Thr	missense_variant	Exon 4 of 15	2		ENSP00000436039.1
UVRAG	ENST00000528264.1	c.83T>C	p.Ile28Thr	missense_variant	Exon 2 of 5	5		ENSP00000433613.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727234

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386T>C (p.I129T) alteration is located in exon 4 (coding exon 4) of the UVRAG gene. This alteration results from a T to C substitution at nucleotide position 386, causing the isoleucine (I) at amino acid position 129 to be replaced by a threonine (T). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Uncertain	0.53
Sift	Benign	0.055	T;T;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.45		Loss of stability (P = 0.0368);.;.;
MVP		0.51
MPC		0.74
ClinPred		0.85	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.30
gMVP		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: rs1259395722; hg19: chr11-75591038;