Genetic Variant R3HDM2:p.Pro827Ser (chr12-57256482-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001394031.1(R3HDM2):c.2479C>T(p.Pro827Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P827P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

R3HDM2
NM_001394031.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Publications

1 publications found

Variant links:

Genes affected

R3HDM2 (HGNC:29167): (R3H domain containing 2) Enables RNA binding activity. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

R3HDM2 links:

ENSG00000258830 (HGNC:):

ENSG00000258830 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394031.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
R3HDM2	NM_001394031.1	MANE Select	c.2479C>T	p.Pro827Ser	missense	Exon 22 of 24	NP_001380960.1	B5MCU0
R3HDM2	NM_001351204.2		c.2635C>T	p.Pro879Ser	missense	Exon 24 of 26	NP_001338133.1
R3HDM2	NM_001351205.2		c.2635C>T	p.Pro879Ser	missense	Exon 23 of 25	NP_001338134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
R3HDM2	ENST00000402412.6	TSL:1 MANE Select	c.2479C>T	p.Pro827Ser	missense	Exon 22 of 24	ENSP00000385839.1	B5MCU0
R3HDM2	ENST00000347140.7	TSL:1	c.2437C>T	p.Pro813Ser	missense	Exon 22 of 24	ENSP00000317903.6	Q9Y2K5-1
R3HDM2	ENST00000393811.6	TSL:1	n.2273C>T		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000137

AC:

AN:

219260

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000636

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:

0.000182

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1443084

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

715890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33048

American (AMR)

AF:

0.0000474

AC:

AN:

42212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.00

AC:

AN:

38976

South Asian (SAS)

AF:

0.00

AC:

AN:

82968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102554

Other (OTH)

AF:

0.0000335

AC:

AN:

59726

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

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

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

2.0

PhyloP100

8.9

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.86

MutPred

0.75

Gain of sheet (P = 0.1945)

MVP

0.69

MPC

1.9

ClinPred

0.92

GERP RS

5.1

Varity_R

0.51

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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