17-32321108-T-C

Position:

• chr17-32321108-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138328.3(RHBDL3):​c.1094T>C​(p.Leu365Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHBDL3 NM_138328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

Genes affected

RHBDL3 (HGNC:16502): (rhomboid like 3) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDL3	NM_138328.3	c.1094T>C	p.Leu365Pro	missense_variant	9/9	ENST00000269051.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDL3	ENST00000269051.9	c.1094T>C	p.Leu365Pro	missense_variant	9/9	1	NM_138328.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Dec 17, 2023

The c.1094T>C (p.L365P) alteration is located in exon 9 (coding exon 9) of the RHBDL3 gene. This alteration results from a T to C substitution at nucleotide position 1094, causing the leucine (L) at amino acid position 365 to be replaced by a proline (P). 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	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.072	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.79		Gain of disorder (P = 0.0081);.;.;
MVP		0.84
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.86

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: chr17-30648127;