12-57268352-C-A

Variant names:

• chr12-57268352-C-A
• NM_001394031.1:c.1981G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394031.1(R3HDM2):​c.1981G>T​(p.Val661Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: R3HDM2 NM_001394031.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10629305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDM2	NM_001394031.1	c.1981G>T	p.Val661Leu	missense_variant	Exon 18 of 24	ENST00000402412.6	NP_001380960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDM2	ENST00000402412.6	c.1981G>T	p.Val661Leu	missense_variant	Exon 18 of 24	1	NM_001394031.1	ENSP00000385839.1
ENSG00000258830	ENST00000548184.1	n.*1031G>T		non_coding_transcript_exon_variant	Exon 8 of 15	2		ENSP00000477227.1
ENSG00000258830	ENST00000548184.1	n.*1031G>T		3_prime_UTR_variant	Exon 8 of 15	2		ENSP00000477227.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1939G>T (p.V647L) alteration is located in exon 16 (coding exon 16) of the R3HDM2 gene. This alteration results from a G to T substitution at nucleotide position 1939, causing the valine (V) at amino acid position 647 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;T;.;T;T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.12	N;N;N;N;.;N;N
REVEL	Benign	0.092
Sift	Benign	0.049	D;D;T;D;.;D;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T
Polyphen		0.017	B;B;.;B;.;.;B
Vest4		0.31
MutPred		0.29		.;.;.;.;.;.;Gain of phosphorylation at Y684 (P = 0.2623);
MVP		0.15
MPC		0.17
ClinPred		0.46	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.060
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: chr12-57662135;