Genetic Variant RNF135:p.His43His (chr17-30971202-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032322.4(RNF135):c.129C>T(p.His43His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,524,090 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

RNF135
NM_032322.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.614

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 17-30971202-C-T is Benign according to our data. Variant chr17-30971202-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 720084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.614 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00524 (798/152298) while in subpopulation AFR AF = 0.0185 (771/41572). AF 95% confidence interval is 0.0175. There are 12 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 798 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.129C>T	p.His43His	synonymous_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.129C>T	p.His43His	synonymous_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

AF:

0.00522

AC:

795

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.00191

GnomAD2 exomes

AF:

0.000655

AC:

AN:

117566

AF XY:

0.000477

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.00115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000229

Gnomad OTH exome

AF:

0.000545

GnomAD4 exome

AF:

0.000459

AC:

630

AN:

1371792

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

264

AN XY:

676668

show subpopulations

African (AFR)

AF:

0.0167

AC:

486

AN:

29178

American (AMR)

AF:

0.00129

AC:

AN:

35002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24656

East Asian (EAS)

AF:

0.00

AC:

AN:

34404

South Asian (SAS)

AF:

0.0000256

AC:

AN:

78008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34300

Middle Eastern (MID)

AF:

0.000635

AC:

AN:

4726

European-Non Finnish (NFE)

AF:

0.0000195

AC:

AN:

1074242

Other (OTH)

AF:

0.00127

AC:

AN:

57276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00524

AC:

798

AN:

152298

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0185

AC:

771

AN:

41572

American (AMR)

AF:

0.00144

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00553

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.3

(source)

DANN

Benign

0.96

PhyloP100

0.61

PromoterAI

0.28

Neutral

(source)

Mutation Taster

=100/0

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

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17-30971202-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over