Genetic Variant NM_032322.4:c.232C>A (chr17-30971305-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_032322.4(RNF135):c.232C>A(p.Leu78Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,381,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Publications

0 publications found

Variant links:

Genes affected

RNF135 (HGNC:21158): (ring finger protein 135) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene is located in a chromosomal region known to be frequently deleted in patients with neurofibromatosis. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

RNF135 Gene-Disease associations (from GenCC):

overgrowth-macrocephaly-facial dysmorphism syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
overgrowth syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RNF135 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22555685).

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.232C>A	p.Leu78Met	missense_variant	Exon 1 of 5	ENST00000328381.10	NP_115698.3	Q8IUD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10 link	c.232C>A	p.Leu78Met	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1381292

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

681906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29032

American (AMR)

AF:

0.00

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24842

East Asian (EAS)

AF:

0.00

AC:

AN:

34508

South Asian (SAS)

AF:

0.00

AC:

AN:

78356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00000465

AC:

AN:

1075452

Other (OTH)

AF:

0.00

AC:

AN:

57338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.232C>A (p.L78M) alteration is located in exon 1 (coding exon 1) of the RNF135 gene. This alteration results from a C to A substitution at nucleotide position 232, causing the leucine (L) at amino acid position 78 to be replaced by a methionine (M). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

T;T;.;.

Eigen

Benign

0.13

Eigen_PC

Benign

-0.0044

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;.;M;M

PhyloP100

1.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.062

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.20

MutPred

0.41

Gain of MoRF binding (P = 0.0697);Gain of MoRF binding (P = 0.0697);Gain of MoRF binding (P = 0.0697);Gain of MoRF binding (P = 0.0697);

MVP

0.31

MPC

0.30

ClinPred

0.97

GERP RS

2.4

PromoterAI

0.0040

Neutral

(source)

Varity_R

0.49

gMVP

0.14

Mutation Taster

=81/19

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_032322.4:c.232C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over