NM_032322.4:c.299A>C

Variant names:

• chr17-30971372-A-C
• rs368080023
• NM_032322.4:c.299A>C

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.299A>C​(p.His100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H100R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.03390518).

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.299A>C	p.His100Pro	missense	Exon 1 of 5	NP_115698.3
	RNF135	NM_001184992.2		c.299A>C	p.His100Pro	missense	Exon 1 of 6	NP_001171921.1	Q8IUD6-3
	RNF135	NM_197939.2		c.299A>C	p.His100Pro	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.299A>C	p.His100Pro	missense	Exon 1 of 5	ENSP00000328340.5	Q8IUD6-1
	RNF135	ENST00000535306.6	TSL:1	c.299A>C	p.His100Pro	missense	Exon 1 of 6	ENSP00000440470.2	Q8IUD6-3
	RNF135	ENST00000324689.8	TSL:1	c.299A>C	p.His100Pro	missense	Exon 1 of 4	ENSP00000323693.4	Q8IUD6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.30
DANN	Benign	0.14
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.20
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.059
Sift	Benign	0.45	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.29		Gain of loop (P = 0.0312)
MVP		0.23
MPC		0.14
ClinPred		0.11	T
GERP RS		-1.2
PromoterAI		0.14	Neutral
Varity_R		0.049
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368080023; hg19: chr17-29298390;