2-135651791-G-A

Position:

• chr2-135651791-G-A

Variant summary

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

The NM_001378107.1(R3HDM1):​c.1787G>A​(p.Gly596Asp) 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: R3HDM1 NM_001378107.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.857

Genes affected

R3HDM1 (HGNC:9757): (R3H domain containing 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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=0.10412145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
R3HDM1	NM_001378107.1	c.1787G>A	p.Gly596Asp	missense_variant	18/27	ENST00000683871.1	NP_001365036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
R3HDM1	ENST00000683871.1	c.1787G>A	p.Gly596Asp	missense_variant	18/27		NM_001378107.1	ENSP00000506980	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

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

May 03, 2023

The c.1682G>A (p.G561D) alteration is located in exon 17 (coding exon 15) of the R3HDM1 gene. This alteration results from a G to A substitution at nucleotide position 1682, causing the glycine (G) at amino acid position 561 to be replaced by an aspartic acid (D). 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	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;T;.;.;.
Eigen	Benign	0.054
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	.;T;T;D;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.87	N;N;N;.;N
REVEL	Benign	0.019
Sift	Uncertain	0.0060	D;D;D;.;D
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.030	.;B;.;.;.
Vest4		0.33
MutPred		0.18		.;Loss of glycosylation at S558 (P = 0.081);.;.;.;
MVP		0.54
MPC		0.38
ClinPred		0.45	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs2065177228; hg19: chr2-136409361;