1-38919188-T-A

Position:

chr1-38919188-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017821.5(RHBDL2):c.25A>T(p.Met9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

RHBDL2
NM_017821.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0520

Variant links:

Genes affected

RHBDL2 (HGNC:16083): (rhomboid like 2) The protein encoded by this gene is a member of the rhomboid family of integral membrane proteins. This family contains proteins that are related to Drosophila rhomboid protein. Members of this family are found in both prokaryotes and eukaryotes and are thought to function as intramembrane serine proteases. The encoded protein is thought to release soluble growth factors by proteolytic cleavage of certain membrane-bound substrates, including ephrin B2 and ephrin B3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

RHBDL2 links:

LOC105378662 (HGNC:):

LOC105378662 links:

RRAGC-DT (HGNC:55793): (RRAGC divergent transcript)

RRAGC-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006894648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RHBDL2	NM_017821.5 linkuse as main transcript	c.25A>T	p.Met9Leu	missense_variant	2/8	ENST00000372990.6
LOC105378662	XR_001737994.2 linkuse as main transcript	n.104T>A		non_coding_transcript_exon_variant	2/2
RHBDL2	NM_001304746.2 linkuse as main transcript	c.265A>T	p.Met89Leu	missense_variant	2/8
LOC105378662	XR_947215.2 linkuse as main transcript	n.130T>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDL2	ENST00000372990.6 linkuse as main transcript	c.25A>T	p.Met9Leu	missense_variant	2/8	5	NM_017821.5	P1	Q9NX52-1
RRAGC-DT	ENST00000667635.1 linkuse as main transcript	n.268-44946T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000711

AC:

108

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251472

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000841

AC:

123

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.000291

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000717

AC:

109

AN:

152122

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.25A>T (p.M9L) alteration is located in exon 2 (coding exon 1) of the RHBDL2 gene. This alteration results from a A to T substitution at nucleotide position 25, causing the methionine (M) at amino acid position 9 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

Benign

0.079

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.0013

T;T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.49

T;.;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

L;L;L

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.018

Sift

Benign

0.76

T;T;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.23

MVP

0.19

MPC

0.059

ClinPred

0.022

GERP RS

0.016

Varity_R

0.058

gMVP

0.33

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