12-57256474-C-G

Variant names:

• chr12-57256474-C-G
• NM_001394031.1:c.2487G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001394031.1(R3HDM2):​c.2487G>C​(p.Gln829His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: R3HDM2 NM_001394031.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.831
• Publications: 0 publications found

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]

ENSG00000258830 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394031.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDM2	NM_001394031.1	MANE Select	c.2487G>C	p.Gln829His	missense	Exon 22 of 24	NP_001380960.1	B5MCU0
	R3HDM2	NM_001351204.2		c.2643G>C	p.Gln881His	missense	Exon 24 of 26	NP_001338133.1
	R3HDM2	NM_001351205.2		c.2643G>C	p.Gln881His	missense	Exon 23 of 25	NP_001338134.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDM2	ENST00000402412.6	TSL:1 MANE Select	c.2487G>C	p.Gln829His	missense	Exon 22 of 24	ENSP00000385839.1	B5MCU0
	R3HDM2	ENST00000347140.7	TSL:1	c.2445G>C	p.Gln815His	missense	Exon 22 of 24	ENSP00000317903.6	Q9Y2K5-1
	R3HDM2	ENST00000393811.6	TSL:1	n.2281G>C		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444938 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717012

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.00 AC: 0 AN: 42508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39062

South Asian (SAS) AF: 0.00 AC: 0 AN: 83140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103486

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.83
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.61		Loss of catalytic residue at Q849 (P = 0.0272)
MVP		0.67
MPC		1.8
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.33
gMVP		0.82
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-57650257;