Genetic Variant NM_172071.4:c.2555G>A (chr1-173947551-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_172071.4(RC3H1):c.2555G>A(p.Arg852Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,613,842 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

RC3H1
NM_172071.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.21

Publications

3 publications found

Variant links:

Genes affected

RC3H1 (HGNC:29434): (ring finger and CCCH-type domains 1) This gene encodes a protein containing RING-type and C3H1-type zinc finger motifs. The encoded protein recognizes and binds to a constitutive decay element (CDE) in the 3' UTR of mRNAs, leading to mRNA deadenylation and degradation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

RC3H1 Gene-Disease associations (from GenCC):

hemophagocytic lymphohistiocytosis, familial, 6
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

RC3H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006665021).

BP6

Variant 1-173947551-C-T is Benign according to our data. Variant chr1-173947551-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2639568.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RC3H1	NM_172071.4 link	c.2555G>A	p.Arg852Gln	missense_variant	Exon 15 of 20	ENST00000367696.7	NP_742068.1	Q5TC82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RC3H1	ENST00000367696.7 link	c.2555G>A	p.Arg852Gln	missense_variant	Exon 15 of 20	5	NM_172071.4	ENSP00000356669.2		Q5TC82-1
RC3H1	ENST00000367694.2 link	c.2555G>A	p.Arg852Gln	missense_variant	Exon 14 of 19	2		ENSP00000356667.2		Q5TC82-2

Frequencies

GnomAD3 genomes

AF:

0.000553

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00112

AC:

282

AN:

251120

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.000449

AC:

657

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000463

AC XY:

337

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

425

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111992

Other (OTH)

AF:

0.00111

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000553

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.000721

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000860

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000972

AC:

118

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RC3H1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;T;.

Eigen

Benign

0.034

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;L

PhyloP100

3.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.96

D;D;D

Vest4

0.15

MVP

0.56

MPC

0.62

ClinPred

0.033

GERP RS

5.9

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.075

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over