16-58687-G-C

Variant names:

• chr16-58687-G-C
• rs1028841930
• NM_022450.5:c.2221C>G

Variant summary

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

The NM_022450.5(RHBDF1):​c.2221C>G​(p.Leu741Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHBDF1 NM_022450.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

Genes affected

RHBDF1 (HGNC:20561): (rhomboid 5 homolog 1) Predicted to enable growth factor binding activity and serine-type endopeptidase activity. Involved in several processes, including negative regulation of protein secretion; regulation of epidermal growth factor receptor signaling pathway; and regulation of proteasomal protein catabolic process. Located in Golgi membrane and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDF1	NM_022450.5	c.2221C>G	p.Leu741Val	missense_variant	Exon 18 of 18	ENST00000262316.10	NP_071895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDF1	ENST00000262316.10	c.2221C>G	p.Leu741Val	missense_variant	Exon 18 of 18	1	NM_022450.5	ENSP00000262316.5
RHBDF1	ENST00000448893.1	c.349C>G	p.Leu117Val	missense_variant	Exon 5 of 5	3		ENSP00000406397.1
RHBDF1	ENST00000428730.5	n.*1535C>G		non_coding_transcript_exon_variant	Exon 17 of 17	5		ENSP00000411508.1
RHBDF1	ENST00000428730.5	n.*1535C>G		3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000411508.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2221C>G (p.L741V) alteration is located in exon 18 (coding exon 17) of the RHBDF1 gene. This alteration results from a C to G substitution at nucleotide position 2221, causing the leucine (L) at amino acid position 741 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	Pathogenic	0.68
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.049	D
Sift4G	Uncertain	0.037	D
Polyphen		0.85	P
Vest4		0.56
MutPred		0.66		Gain of MoRF binding (P = 0.116);
MVP		0.57
MPC		1.1
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.27
gMVP		0.77

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: rs1028841930; hg19: chr16-108686;