Genetic Variant R3HCC1:p.Cys362Phe (chr8-23293362-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001136108.3(R3HCC1):c.1085G>T(p.Cys362Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,398,988 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: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

R3HCC1
NM_001136108.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.10

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32486933).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136108.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
R3HCC1	NM_001136108.3	MANE Select	c.1085G>T	p.Cys362Phe	missense	Exon 6 of 8	NP_001129580.2	Q9Y3T6-1
R3HCC1	NM_001301650.2		c.959G>T	p.Cys320Phe	missense	Exon 7 of 9	NP_001288579.1	Q9Y3T6-3
R3HCC1	NR_125897.1		n.1054G>T		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
R3HCC1	ENST00000265806.12	TSL:1 MANE Select	c.1085G>T	p.Cys362Phe	missense	Exon 6 of 8	ENSP00000265806.8	Q9Y3T6-1
R3HCC1	ENST00000625275.3	TSL:1	c.959G>T	p.Cys320Phe	missense	Exon 7 of 9	ENSP00000486278.2	Q9Y3T6-3
R3HCC1	ENST00000522012.6	TSL:1	n.*364G>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000487121.2	A0A0D9SG39

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000649

AC:

AN:

154164

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1398988

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690010

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000317

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35724

South Asian (SAS)

AF:

0.00

AC:

AN:

79218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078800

Other (OTH)

AF:

0.00

AC:

AN:

57996

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.028

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.69

PhyloP100

7.1

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.28

Sift

Benign

0.037

Sift4G

Uncertain

0.042

Vest4

0.58

MutPred

0.38

Loss of catalytic residue at L403 (P = 0.0376)

MVP

0.30

ClinPred

0.93

GERP RS

5.8

gMVP

0.44

Mutation Taster

=74/26

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over