chr20-31482387-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014012.6(REM1):​c.524T>C​(p.Leu175Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

REM1
NM_014012.6 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83
Variant links:
Genes affected
REM1 (HGNC:15922): (RRAD and GEM like GTPase 1) The protein encoded by this gene is a GTPase and member of the RAS-like GTP-binding protein family. The encoded protein is expressed in endothelial cells, where it promotes reorganization of the actin cytoskeleton and morphological changes in the cells. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
REM1NM_014012.6 linkuse as main transcriptc.524T>C p.Leu175Pro missense_variant 4/5 ENST00000201979.3 NP_054731.2 O75628
REM1XM_005260404.1 linkuse as main transcriptc.548T>C p.Leu183Pro missense_variant 4/5 XP_005260461.1
REM1XM_017027833.2 linkuse as main transcriptc.548T>C p.Leu183Pro missense_variant 4/5 XP_016883322.1
REM1XM_011528795.1 linkuse as main transcriptc.542T>C p.Leu181Pro missense_variant 4/5 XP_011527097.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
REM1ENST00000201979.3 linkuse as main transcriptc.524T>C p.Leu175Pro missense_variant 4/51 NM_014012.6 ENSP00000201979.2 O75628

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 03, 2023The c.524T>C (p.L175P) alteration is located in exon 4 (coding exon 3) of the REM1 gene. This alteration results from a T to C substitution at nucleotide position 524, causing the leucine (L) at amino acid position 175 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
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.84
Gain of disorder (P = 0.0221);
MVP
0.97
MPC
1.0
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.96
gMVP
0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-30070190; API