Genetic Variant R3HCC1:p.Arg401Cys (chr8-23295975-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136108.3(R3HCC1):c.1201C>T(p.Arg401Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,549,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R401H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

R3HCC1
NM_001136108.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.98

Variant links:

Genes affected

R3HCC1 (HGNC:27329): (R3H domain and coiled-coil containing 1) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

R3HCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.22570291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HCC1	NM_001136108.3 link	c.1201C>T	p.Arg401Cys	missense_variant	Exon 8 of 8	ENST00000265806.12	NP_001129580.2	Q9Y3T6-1
R3HCC1	NM_001301650.2 link	c.1075C>T	p.Arg359Cys	missense_variant	Exon 9 of 9		NP_001288579.1	Q9Y3T6-3
R3HCC1	NR_125897.1 link	n.1170C>T		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HCC1	ENST00000265806.12 link	c.1201C>T	p.Arg401Cys	missense_variant	Exon 8 of 8	1	NM_001136108.3	ENSP00000265806.8		Q9Y3T6-1A0A0R4J2E2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

150096

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

80030

show subpopulations

Gnomad AFR exome

AF:

0.000129

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:

0.000263

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000235

GnomAD4 exome

AF:

0.000159

AC:

222

AN:

1397240

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

122

AN XY:

689114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.000144

Gnomad4 NFE exome

AF:

0.000185

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.000171

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640C>T (p.R214C) alteration is located in exon 8 (coding exon 5) of the R3HCC1 gene. This alteration results from a C to T substitution at nucleotide position 640, causing the arginine (R) at amino acid position 214 to be replaced by a cysteine (C). 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

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Benign

0.017

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-4.5

.;.;D

REVEL

Benign

0.18

Sift

Uncertain

0.0010

.;.;D

Sift4G

Uncertain

0.0080

D;D;D

Vest4

0.21

MVP

0.26

ClinPred

0.63

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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