12-57256482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000402412.6(R3HDM2):​c.2479C>T​(p.Pro827Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

R3HDM2
ENST00000402412.6 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94
Variant links:
Genes affected
R3HDM2 (HGNC:29167): (R3H domain containing 2) Enables RNA binding activity. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
R3HDM2NM_001394031.1 linkuse as main transcriptc.2479C>T p.Pro827Ser missense_variant 22/24 ENST00000402412.6 NP_001380960.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
R3HDM2ENST00000402412.6 linkuse as main transcriptc.2479C>T p.Pro827Ser missense_variant 22/241 NM_001394031.1 ENSP00000385839 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000346
AC:
5
AN:
1443084
Hom.:
0
Cov.:
30
AF XY:
0.00000279
AC XY:
2
AN XY:
715890
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000474
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:
9.07e-7
Gnomad4 OTH exome
AF:
0.0000335
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000756

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 GeneticsSep 16, 2021The c.2437C>T (p.P813S) alteration is located in exon 20 (coding exon 20) of the R3HDM2 gene. This alteration results from a C to T substitution at nucleotide position 2437, causing the proline (P) at amino acid position 813 to be replaced by a serine (S). 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
0.92
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.33
T;T;.;T;T;T;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
.;D;D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Benign
2.0
M;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-4.3
D;D;D;D;.;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0020
D;D;D;D;.;D;D
Sift4G
Uncertain
0.0070
D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;.;D
Vest4
0.86
MutPred
0.75
.;.;.;.;.;.;Gain of sheet (P = 0.1945);
MVP
0.69
MPC
1.9
ClinPred
0.92
D
GERP RS
5.1
Varity_R
0.51
gMVP
0.61

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

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

Other links and lift over

dbSNP: rs1232209458; hg19: chr12-57650265; API