Variant 19-899604-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138774.4(R3HDM4):c.644A>C(p.Asn215Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,460,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

R3HDM4
NM_138774.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.566

Variant links:

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]

R3HDM4 links:

R3HDM4 (HGNC:):

R3HDM4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26652947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
R3HDM4	NM_138774.4 linkuse as main transcript	c.644A>C	p.Asn215Thr	missense_variant	6/8	ENST00000361574.10	NP_620129.2	Q96D70
R3HDM4	XM_011528416.3 linkuse as main transcript	c.644A>C	p.Asn215Thr	missense_variant	6/8		XP_011526718.1
R3HDM4	XM_024451771.2 linkuse as main transcript	c.278A>C	p.Asn93Thr	missense_variant	6/8		XP_024307539.1
R3HDM4	XM_047439659.1 linkuse as main transcript	c.278A>C	p.Asn93Thr	missense_variant	5/7		XP_047295615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
R3HDM4	ENST00000361574.10 linkuse as main transcript	c.644A>C	p.Asn215Thr	missense_variant	6/8	1	NM_138774.4	ENSP00000355385.4		Q96D70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246636

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1460238

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726444

show subpopulations

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.644A>C (p.N215T) alteration is located in exon 6 (coding exon 6) of the R3HDM4 gene. This alteration results from a A to C substitution at nucleotide position 644, causing the asparagine (N) at amino acid position 215 to be replaced by a threonine (T). 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

0.18

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.0081

T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.71

N;.

REVEL

Benign

0.059

Sift

Benign

0.47

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.80

P;.

Vest4

0.51

MutPred

0.22

Gain of helix (P = 0.1736);.;

MVP

0.35

MPC

0.13

ClinPred

0.12

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over