2-135641682-G-C

Position:

• chr2-135641682-G-C

Variant summary

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

The NM_001378107.1(R3HDM1):​c.1366G>C​(p.Asp456His) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: R3HDM1 NM_001378107.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
R3HDM1	NM_001378107.1	c.1366G>C	p.Asp456His	missense_variant	15/27	ENST00000683871.1	NP_001365036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
R3HDM1	ENST00000683871.1	c.1366G>C	p.Asp456His	missense_variant	15/27		NM_001378107.1	ENSP00000506980	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 12, 2021

The c.1366G>C (p.D456H) alteration is located in exon 15 (coding exon 13) of the R3HDM1 gene. This alteration results from a G to C substitution at nucleotide position 1366, causing the aspartic acid (D) at amino acid position 456 to be replaced by a histidine (H). 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	0.31
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.68
MutPred		0.35		Loss of stability (P = 0.0811);.;Loss of stability (P = 0.0811);
MVP		0.43
MPC		0.93
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.29
gMVP		0.48

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: rs2063803463; hg19: chr2-136399252;