22-29260741-C-T

Variant names:

• chr22-29260741-C-T
• NM_012265.3:c.656G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012265.3(RHBDD3):​c.656G>A​(p.Ser219Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: RHBDD3 NM_012265.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256
• Publications: 0 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]

ENSG00000237015 (HGNC:):

ACMG classification

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=0.07435349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3	c.656G>A	p.Ser219Asn	missense_variant	Exon 5 of 7	ENST00000216085.12	NP_036397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDD3	ENST00000216085.12	c.656G>A	p.Ser219Asn	missense_variant	Exon 5 of 7	1	NM_012265.3	ENSP00000216085.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.656G>A (p.S219N) alteration is located in exon 5 (coding exon 3) of the RHBDD3 gene. This alteration results from a G to A substitution at nucleotide position 656, causing the serine (S) at amino acid position 219 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.6
DANN	Benign	0.81
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.26
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.045
Sift	Benign	0.33	T
Sift4G	Benign	0.14	T
Polyphen		0.18	B
Vest4		0.058
MutPred		0.15		Loss of glycosylation at S219 (P = 0.0239);
MVP		0.27
MPC		0.013
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.066
gMVP		0.28
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr22-29656730;