Genetic Variant NM_172071.4:c.2414A>G (chr1-173952095-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_172071.4(RC3H1):c.2414A>G(p.Asn805Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,597,116 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

RC3H1
NM_172071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22123149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RC3H1	NM_172071.4 link	c.2414A>G	p.Asn805Ser	missense_variant	Exon 14 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.2414A>G	p.Asn805Ser	missense_variant	Exon 14 of 20	5	NM_172071.4	ENSP00000356669.2		Q5TC82-1
RC3H1	ENST00000367694.2 link	c.2414A>G	p.Asn805Ser	missense_variant	Exon 13 of 19	2		ENSP00000356667.2		Q5TC82-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242824

AF XY:

0.00000760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000312

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1445772

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

718914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33036

American (AMR)

AF:

0.0000921

AC:

AN:

43454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25678

East Asian (EAS)

AF:

0.00

AC:

AN:

39222

South Asian (SAS)

AF:

0.00

AC:

AN:

82858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103346

Other (OTH)

AF:

0.0000168

AC:

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151344

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41174

American (AMR)

AF:

0.000198

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2414A>G (p.N805S) alteration is located in exon 13 (coding exon 13) of the RC3H1 gene. This alteration results from a A to G substitution at nucleotide position 2414, causing the asparagine (N) at amino acid position 805 to be replaced by a serine (S). 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

0.072

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Benign

0.0055

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

6.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.054

T;T;D

Sift4G

Benign

0.37

T;T;T

Polyphen

0.33

B;B;P

Vest4

0.068

MutPred

0.61

Gain of disorder (P = 0.0435);Gain of disorder (P = 0.0435);Gain of disorder (P = 0.0435);

MVP

0.59

MPC

0.25

ClinPred

0.27

GERP RS

5.9

Varity_R

0.11

gMVP

0.17

Mutation Taster

=95/5

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over