2-226995484-A-G

Variant summary

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

The NM_001167608.3(RHBDD1):c.910A>G(p.Met304Val) variant causes a missense change. 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: 4.62

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]

COL4A4 (HGNC:):

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=0.10072306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDD1	NM_001167608.3	c.910A>G	p.Met304Val	missense_variant	9/9	ENST00000392062.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDD1	ENST00000392062.7	c.910A>G	p.Met304Val	missense_variant	9/9	5	NM_001167608.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Sep 17, 2021

The c.910A>G (p.M304V) alteration is located in exon 9 (coding exon 6) of the RHBDD1 gene. This alteration results from a A to G substitution at nucleotide position 910, causing the methionine (M) at amino acid position 304 to be replaced by a valine (V). 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	0.00090	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.00025	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.73	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.094
Sift	Benign	0.12	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0030	B;B
Vest4		0.44
MutPred		0.18		Loss of MoRF binding (P = 0.0947);Loss of MoRF binding (P = 0.0947);
MVP		0.20
MPC		0.049
ClinPred		0.71	D
GERP RS		5.4
Varity_R		0.25
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-227860200;