dbSNP rs201259415: RHBDD3:p.Pro256Ser (chr22-29260543-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012265.3(RHBDD3):c.766C>T(p.Pro256Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P256A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHBDD3
NM_012265.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.408

Publications

3 publications found

Variant links:

Genes affected

RHBDD3 (HGNC:1308): (rhomboid domain containing 3) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within several processes, including liver development; negative regulation of natural killer cell activation; and positive regulation of protein catabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RHBDD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047189534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3 link	c.766C>T	p.Pro256Ser	missense_variant	Exon 6 of 7	ENST00000216085.12	NP_036397.1	Q9Y3P4A0A024R1J2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RHBDD3	ENST00000216085.12 link	c.766C>T	p.Pro256Ser	missense_variant	Exon 6 of 7	1	NM_012265.3	ENSP00000216085.7	Q9Y3P4
RHBDD3	ENST00000413137.6 link	n.*342C>T		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000399550.2	F8WFA9
RHBDD3	ENST00000496342.1 link	n.805C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2
RHBDD3	ENST00000413137.6 link	n.*342C>T		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000399550.2	F8WFA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000910

AC:

AN:

219770

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445458

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

42320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39382

South Asian (SAS)

AF:

0.0000238

AC:

AN:

83872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107022

Other (OTH)

AF:

0.00

AC:

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.050

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.011

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.37

M_CAP

Benign

0.0044

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.41

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.81

REVEL

Benign

0.026

Sift

Benign

0.17

Sift4G

Benign

0.084

Polyphen

0.0

Vest4

0.11

MutPred

0.10

Loss of catalytic residue at P256 (P = 0.0016);

MVP

0.099

MPC

0.013

ClinPred

0.017

GERP RS

-5.8

Varity_R

0.025

gMVP

0.24

Mutation Taster

=98/2

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

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rs201259415

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over