2-226864823-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001167608.3(RHBDD1):c.130A>T(p.Asn44Tyr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHBDD1 NM_001167608.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

Genes affected

RHBDD1 (HGNC:23081): (rhomboid domain containing 1) Enables serine-type endopeptidase activity. Involved in several processes, including cellular response to unfolded protein; membrane protein proteolysis; and positive regulation of protein catabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13173151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDD1	NM_001167608.3	c.130A>T	p.Asn44Tyr	missense_variant	4/9	ENST00000392062.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDD1	ENST00000392062.7	c.130A>T	p.Asn44Tyr	missense_variant	4/9	5	NM_001167608.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.130A>T (p.N44Y) alteration is located in exon 4 (coding exon 1) of the RHBDD1 gene. This alteration results from a A to T substitution at nucleotide position 130, causing the asparagine (N) at amino acid position 44 to be replaced by a tyrosine (Y). 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	0.059
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Benign	0.77
Eigen	Benign	-0.084
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;.;T;T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.58	T;T;T;D;T;T;D
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.41, 0.18	.;B;B;.;B;.;.
Vest4		0.29, 0.28
MutPred		0.46		Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);Gain of catalytic residue at P48 (P = 0.0807);
MVP		0.39
MPC		0.056
ClinPred		0.26	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1559208370; hg19: chr2-227729539;