chr12-57256482-G-A

Position:

• chr12-57256482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94

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 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
R3HDM2	NM_001394031.1	c.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
R3HDM2	ENST00000402412.6	c.2479C>T	p.Pro827Ser	missense_variant	22/24	1	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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The 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

Other links and lift over

dbSNP: rs1232209458; hg19: chr12-57650265;