19-900886-C-T

Variant summary

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

The NM_138774.4(R3HDM4):c.418G>A(p.Glu140Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,442,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: R3HDM4 NM_138774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

R3HDM4 (HGNC:28270): (R3H domain containing 4) Predicted to enable nucleic acid binding activity. Predicted to be located in nucleus. [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=0.10365221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
R3HDM4	NM_138774.4	c.418G>A	p.Glu140Lys	missense_variant	4/8	ENST00000361574.10
R3HDM4	XM_011528416.3	c.418G>A	p.Glu140Lys	missense_variant	4/8
R3HDM4	XM_024451771.2	c.52G>A	p.Glu18Lys	missense_variant	4/8
R3HDM4	XM_047439659.1	c.52G>A	p.Glu18Lys	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
R3HDM4	ENST00000361574.10	c.418G>A	p.Glu140Lys	missense_variant	4/8	1	NM_138774.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1442098 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 715656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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 21, 2022

The c.418G>A (p.E140K) alteration is located in exon 4 (coding exon 4) of the R3HDM4 gene. This alteration results from a G to A substitution at nucleotide position 418, causing the glutamic acid (E) at amino acid position 140 to be replaced by a lysine (K). 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	0.081
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.13
Sift	Benign	0.072	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.30	B;.
Vest4		0.30
MutPred		0.28		Gain of MoRF binding (P = 0.019);.;
MVP		0.22
MPC		0.14
ClinPred		0.44	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-900886;