rs7225888

Variant names:

• chr17-30971286-C-A
• rs7225888
• NM_032322.4:c.213C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-30971286-C-A
• chr17-30971286-C-G
• chr17-30971286-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032322.4(RNF135):​c.213C>A​(p.His71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 0 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae)
• overgrowth syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024488628).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032322.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF135	NM_032322.4	MANE Select	c.213C>A	p.His71Gln	missense	Exon 1 of 5	NP_115698.3
	RNF135	NM_001184992.2		c.213C>A	p.His71Gln	missense	Exon 1 of 6	NP_001171921.1	Q8IUD6-3
	RNF135	NM_197939.2		c.213C>A	p.His71Gln	missense	Exon 1 of 4	NP_922921.1	Q8IUD6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF135	ENST00000328381.10	TSL:1 MANE Select	c.213C>A	p.His71Gln	missense	Exon 1 of 5	ENSP00000328340.5	Q8IUD6-1
	RNF135	ENST00000535306.6	TSL:1	c.213C>A	p.His71Gln	missense	Exon 1 of 6	ENSP00000440470.2	Q8IUD6-3
	RNF135	ENST00000324689.8	TSL:1	c.213C>A	p.His71Gln	missense	Exon 1 of 4	ENSP00000323693.4	Q8IUD6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375182 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 678744

African (AFR) AF: 0.0000355 AC: 1 AN: 28198

American (AMR) AF: 0.00 AC: 0 AN: 34434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24630

East Asian (EAS) AF: 0.00 AC: 0 AN: 33790

South Asian (SAS) AF: 0.00 AC: 0 AN: 77724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4140

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073410

Other (OTH) AF: 0.00 AC: 0 AN: 57084

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	4.4
DANN	Benign	0.52
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.063	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.086
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.11
Sift	Benign	0.76	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.12		Gain of ubiquitination at K74 (P = 0.0545)
MVP		0.30
MPC		0.090
ClinPred		0.068	T
GERP RS		3.5
PromoterAI		0.25	Neutral
Varity_R		0.047
gMVP		0.056

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

Other links and lift over

dbSNP: rs7225888; hg19: chr17-29298304;