12-57256446-G-A

Position:

• chr12-57256446-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000402412.6(R3HDM2):​c.2515C>T​(p.Leu839Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: R3HDM2 ENST00000402412.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
R3HDM2	NM_001394031.1	c.2515C>T	p.Leu839Phe	missense_variant	22/24	ENST00000402412.6	NP_001380960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
R3HDM2	ENST00000402412.6	c.2515C>T	p.Leu839Phe	missense_variant	22/24	1	NM_001394031.1	ENSP00000385839	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446216 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717794

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.2473C>T (p.L825F) 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 2473, causing the leucine (L) at amino acid position 825 to be replaced by a phenylalanine (F). 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	Benign	0.16
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T;T;.;T;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L;L;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;N;N;.;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;D;D;D;.;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		0.91	P;P;.;P;.;.;D
Vest4		0.38
MutPred		0.28		.;.;.;.;.;.;Loss of disorder (P = 0.0721);
MVP		0.72
MPC		1.6
ClinPred		0.93	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs865863968; hg19: chr12-57650229;