22-29260440-G-A

Variant names:

• chr22-29260440-G-A
• rs765758644
• NM_012265.3:c.869C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012265.3(RHBDD3):​c.869C>T​(p.Ala290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,611,332 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: RHBDD3 NM_012265.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0400
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032987714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3	c.869C>T	p.Ala290Val	missense_variant	Exon 6 of 7	ENST00000216085.12	NP_036397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDD3	ENST00000216085.12	c.869C>T	p.Ala290Val	missense_variant	Exon 6 of 7	1	NM_012265.3	ENSP00000216085.7
RHBDD3	ENST00000413137.6	n.*445C>T		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000399550.2
RHBDD3	ENST00000413137.6	n.*445C>T		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000399550.2
RHBDD3	ENST00000496342.1	n.*59C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000574 AC: 14 AN: 243760 AF XY: 0.0000907

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: 0.0000965

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1459170 Hom.: 0 Cov.: 33 AF XY: 0.0000510 AC XY: 37 AN XY: 725750

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000350 AC: 30 AN: 85808

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111464

Other (OTH) AF: 0.0000332 AC: 2 AN: 60284

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.869C>T (p.A290V) alteration is located in exon 6 (coding exon 4) of the RHBDD3 gene. This alteration results from a C to T substitution at nucleotide position 869, causing the alanine (A) at amino acid position 290 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.5
DANN	Benign	0.96
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.040
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.024
Sift	Benign	0.066	T
Sift4G	Uncertain	0.037	D
Polyphen		0.0	B
Vest4		0.15
MVP		0.29
MPC		0.013
ClinPred		0.031	T
GERP RS		-1.1
Varity_R		0.029
gMVP		0.32
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765758644; hg19: chr22-29656429; COSMIC: COSV53324472; COSMIC: COSV53324472;