12-57254990-C-A

Variant names:

• chr12-57254990-C-A
• NM_001394031.1:c.2756G>T

Variant summary

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

The NM_001394031.1(R3HDM2):​c.2756G>T​(p.Gly919Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: R3HDM2 NM_001394031.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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

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 rank	MANE	Protein	UniProt
R3HDM2	NM_001394031.1	c.2756G>T	p.Gly919Val	missense_variant	Exon 24 of 24	ENST00000402412.6	NP_001380960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDM2	ENST00000402412.6	c.2756G>T	p.Gly919Val	missense_variant	Exon 24 of 24	1	NM_001394031.1	ENSP00000385839.1
ENSG00000258830	ENST00000548184.1	n.*1682+1000G>T		intron_variant	Intron 13 of 14	2		ENSP00000477227.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2714G>T (p.G905V) alteration is located in exon 22 (coding exon 22) of the R3HDM2 gene. This alteration results from a G to T substitution at nucleotide position 2714, causing the glycine (G) at amino acid position 905 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T;.;T;T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;L;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N;N;N;N;.;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.017	D;D;D;D;.;D;D
Sift4G	Uncertain	0.049	D;D;T;T;D;T;D
Polyphen		0.96	D;D;.;P;.;.;P
Vest4		0.47
MutPred		0.34		.;.;.;.;.;.;Loss of disorder (P = 0.0139);
MVP		0.59
MPC		1.8
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.47
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: 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: chr12-57648773;