16-60511-G-A

Position:

• chr16-60511-G-A

Variant summary

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

The NM_022450.5(RHBDF1):​c.1586C>T​(p.Pro529Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHBDF1 NM_022450.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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]

RHBDF1 (HGNC:):

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/exons	MANE	Protein	UniProt
RHBDF1	NM_022450.5	c.1586C>T	p.Pro529Leu	missense_variant	12/18	ENST00000262316.10	NP_071895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHBDF1	ENST00000262316.10	c.1586C>T	p.Pro529Leu	missense_variant	12/18	1	NM_022450.5	ENSP00000262316.5
RHBDF1	ENST00000428730.5	n.*900C>T		non_coding_transcript_exon_variant	11/17	5		ENSP00000411508.1
RHBDF1	ENST00000493647.1	n.170C>T		non_coding_transcript_exon_variant	1/4	3
RHBDF1	ENST00000428730.5	n.*900C>T		3_prime_UTR_variant	11/17	5		ENSP00000411508.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 20, 2023

The c.1586C>T (p.P529L) alteration is located in exon 12 (coding exon 11) of the RHBDF1 gene. This alteration results from a C to T substitution at nucleotide position 1586, causing the proline (P) at amino acid position 529 to be replaced by a leucine (L). 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	0.76
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D
Sift4G	Benign	0.25	T
Polyphen		0.66	P
Vest4		0.74
MutPred		0.48		Loss of sheet (P = 3e-04);
MVP		0.53
MPC		1.1
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.84

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: chr16-110509;