NM_012265.3:c.1052G>T

Variant names:

• chr22-29260169-C-A
• rs370993074
• NM_012265.3:c.1052G>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.1052G>T​(p.Arg351Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,589,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R351H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: RHBDD3 NM_012265.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 2 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=0.00834772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3	c.1052G>T	p.Arg351Leu	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.1052G>T	p.Arg351Leu	missense_variant	Exon 7 of 7	1	NM_012265.3	ENSP00000216085.7
RHBDD3	ENST00000413137.6	n.*628G>T		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000399550.2
RHBDD3	ENST00000413137.6	n.*628G>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000399550.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152248 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: 0.00385

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000214 AC: 44 AN: 205630 AF XY: 0.000180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.000389

GnomAD4 exome AF: 0.0000988 AC: 142 AN: 1436964 Hom.: 0 Cov.: 30 AF XY: 0.000115 AC XY: 82 AN XY: 712474

African (AFR) AF: 0.0000302 AC: 1 AN: 33094

American (AMR) AF: 0.00 AC: 0 AN: 40986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00101 AC: 39 AN: 38562

South Asian (SAS) AF: 0.000519 AC: 43 AN: 82774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000818 AC: 9 AN: 1099862

Other (OTH) AF: 0.000842 AC: 50 AN: 59390

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000241 AC: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.065
Sift	Benign	0.039	D
Sift4G	Uncertain	0.019	D
Polyphen		0.83	P
Vest4		0.33
MVP		0.48
MPC		0.056
ClinPred		0.098	T
GERP RS		1.4
Varity_R		0.080
gMVP		0.30
Mutation Taster		=77/23	polymorphism

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: rs370993074; hg19: chr22-29656158;