22-29260206-T-C

Variant names:

• chr22-29260206-T-C
• rs554491048
• NM_012265.3:c.1015A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012265.3(RHBDD3):​c.1015A>G​(p.Thr339Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000313 in 1,598,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: RHBDD3 NM_012265.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088525355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3	c.1015A>G	p.Thr339Ala	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.1015A>G	p.Thr339Ala	missense_variant	Exon 7 of 7	1	NM_012265.3	ENSP00000216085.7
RHBDD3	ENST00000413137.6	n.*591A>G		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000399550.2
RHBDD3	ENST00000413137.6	n.*591A>G		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000399550.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000590 AC: 13 AN: 220262 AF XY: 0.0000419

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000783

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000318 AC: 46 AN: 1445928 Hom.: 0 Cov.: 30 AF XY: 0.0000320 AC XY: 23 AN XY: 717822

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.0000238 AC: 1 AN: 41940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.00105 AC: 41 AN: 39100

South Asian (SAS) AF: 0.00 AC: 0 AN: 83762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105008

Other (OTH) AF: 0.0000669 AC: 4 AN: 59756

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

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

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015A>G (p.T339A) alteration is located in exon 7 (coding exon 5) of the RHBDD3 gene. This alteration results from a A to G substitution at nucleotide position 1015, causing the threonine (T) at amino acid position 339 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.29
MutPred		0.36		Gain of catalytic residue at M335 (P = 0.0177);
MVP		0.55
MPC		0.031
ClinPred		0.21	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.45
Mutation Taster		=46/54	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

dbSNP: rs554491048; hg19: chr22-29656195;