rs1057519367

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP5_ModerateBP4BS2

The NM_001372078.1(REV3L):​c.559A>T​(p.Arg187Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,435,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

REV3L
NM_001372078.1 missense

Scores

1
6
11

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.81
Variant links:
Genes affected
REV3L (HGNC:9968): (REV3 like, DNA directed polymerase zeta catalytic subunit) The protein encoded by this gene represents the catalytic subunit of DNA polymerase zeta, which functions in translesion DNA synthesis. The encoded protein can be found in mitochondria, where it protects DNA from damage. Defects in this gene are a cause of Mobius syndrome. [provided by RefSeq, Jan 2017]
MFSD4B (HGNC:21053): (major facilitator superfamily domain containing 4B) Predicted to enable glucose transmembrane transporter activity. Predicted to be involved in glucose transmembrane transport and sodium ion transport. Predicted to be located in apical plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), REV3L. . Gene score misZ 2.4677 (greater than the threshold 3.09). Trascript score misZ 3.98 (greater than threshold 3.09). GenCC has associacion of gene with Mobius syndrome.
PP5
Variant 6-111405476-T-A is Pathogenic according to our data. Variant chr6-111405476-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221624.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.26964152). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
REV3LNM_001372078.1 linkuse as main transcriptc.559A>T p.Arg187Trp missense_variant 4/32 ENST00000368802.8 NP_001359007.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
REV3LENST00000368802.8 linkuse as main transcriptc.559A>T p.Arg187Trp missense_variant 4/321 NM_001372078.1 ENSP00000357792 P4O60673-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000870
AC:
2
AN:
229940
Hom.:
0
AF XY:
0.0000161
AC XY:
2
AN XY:
124268
show subpopulations
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:
0.0000185
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000766
AC:
11
AN:
1435434
Hom.:
0
Cov.:
30
AF XY:
0.0000140
AC XY:
10
AN XY:
712856
show subpopulations
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:
0.00000997
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Carcinoma of colon Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i SunyerNov 01, 2015Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for prostate cancer -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.34
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T;T;.;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;.;D;D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.27
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.81
D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.3
N;N;N;N
REVEL
Benign
0.15
Sift
Uncertain
0.0090
D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.49
MutPred
0.48
Loss of disorder (P = 0.0019);Loss of disorder (P = 0.0019);.;Loss of disorder (P = 0.0019);
MVP
0.082
MPC
0.37
ClinPred
0.85
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519367; hg19: chr6-111726679; API