22-29260197-C-T

Variant names:

• chr22-29260197-C-T
• NM_012265.3:c.1024G>A

Variant summary

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

The NM_012265.3(RHBDD3):​c.1024G>A​(p.Ala342Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A342V) has been classified 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: 6.54
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3	c.1024G>A	p.Ala342Thr	missense_variant	Exon 7 of 7	ENST00000216085.12	NP_036397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDD3	ENST00000216085.12	c.1024G>A	p.Ala342Thr	missense_variant	Exon 7 of 7	1	NM_012265.3	ENSP00000216085.7
RHBDD3	ENST00000413137.6	n.*600G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000399550.2
RHBDD3	ENST00000413137.6	n.*600G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000399550.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1024G>A (p.A342T) alteration is located in exon 7 (coding exon 5) of the RHBDD3 gene. This alteration results from a G to A substitution at nucleotide position 1024, causing the alanine (A) at amino acid position 342 to be replaced by a threonine (T). 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	Pathogenic	0.81
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.62		Gain of phosphorylation at A342 (P = 0.0595);
MVP		0.65
MPC		0.093
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.53
Mutation Taster		=43/57	disease causing

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

Other links and lift over

hg19: chr22-29656186;