2-226914315-C-T

Position:

• chr2-226914315-C-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.820C>T​(p.Leu274Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHBDD1 NM_001167608.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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=0.24417785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHBDD1	NM_001167608.3	c.820C>T	p.Leu274Phe	missense_variant	8/9	ENST00000392062.7	NP_001161080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHBDD1	ENST00000392062.7	c.820C>T	p.Leu274Phe	missense_variant	8/9	5	NM_001167608.3	ENSP00000375914	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461296 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Jun 29, 2023

The c.820C>T (p.L274F) alteration is located in exon 8 (coding exon 5) of the RHBDD1 gene. This alteration results from a C to T substitution at nucleotide position 820, causing the leucine (L) at amino acid position 274 to be replaced by a phenylalanine (F). 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	0.18
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0040	T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.92	P;P;.
Vest4		0.27
MutPred		0.30		Loss of phosphorylation at S269 (P = 0.2424);Loss of phosphorylation at S269 (P = 0.2424);.;
MVP		0.51
MPC		0.078
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.081
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs1948739074; hg19: chr2-227779031;