Variant 17-32266296-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138328.3(RHBDL3):c.107A>C(p.Glu36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,454,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RHBDL3
NM_138328.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.85

Variant links:

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]

RHBDL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013210207).

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHBDL3	NM_138328.3 linkuse as main transcript	c.107A>C	p.Glu36Ala	missense_variant	1/9	ENST00000269051.9	NP_612201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHBDL3	ENST00000269051.9 linkuse as main transcript	c.107A>C	p.Glu36Ala	missense_variant	1/9	1	NM_138328.3	ENSP00000269051	P1	P58872-1
RHBDL3	ENST00000431505.6 linkuse as main transcript	c.107A>C	p.Glu36Ala	missense_variant	1/8	1		ENSP00000394849
RHBDL3	ENST00000538145.5 linkuse as main transcript	c.107A>C	p.Glu36Ala	missense_variant	1/8	1		ENSP00000442092		P58872-3
RHBDL3	ENST00000578006.5 linkuse as main transcript	c.107A>C	p.Glu36Ala	missense_variant, NMD_transcript_variant	1/9	1		ENSP00000463941

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

151726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000702

AC:

AN:

71260

Hom.:

AF XY:

0.0000488

AC XY:

AN XY:

40960

show subpopulations

Gnomad AFR exome

AF:

0.00348

Gnomad AMR exome

AF:

0.0000687

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000483

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1303012

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

642866

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.0000782

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000138

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000111

GnomAD4 genome

AF:

0.000310

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000363

ExAC

AF:

0.0000448

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2021

The c.107A>C (p.E36A) alteration is located in exon 1 (coding exon 1) of the RHBDL3 gene. This alteration results from a A to C substitution at nucleotide position 107, causing the glutamic acid (E) at amino acid position 36 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.017

T;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.60

T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.4

.;L;L

MutationTaster

Benign

0.94

D;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.082

Sift

Uncertain

0.029

D;T;T

Sift4G

Uncertain

0.028

D;T;T

Polyphen

0.65

.;P;.

Vest4

0.18, 0.17

MutPred

0.51

Loss of solvent accessibility (P = 0.0224);Loss of solvent accessibility (P = 0.0224);Loss of solvent accessibility (P = 0.0224);

MVP

0.85

MPC

0.62

ClinPred

0.035

GERP RS

2.5

Varity_R

0.14

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over