16-30764383-G-C

Variant names:

• chr16-30764383-G-C
• rs564363255
• NM_014771.4:c.647G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014771.4(RNF40):​c.647G>C​(p.Arg216Pro) variant causes a missense, splice region 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. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF40 NM_014771.4 missense, splice_region
• Scores: Splicing: ADA: 0.5985
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

Genes affected

RNF40 (HGNC:16867): (ring finger protein 40) The protein encoded by this gene contains a RING finger, a motif known to be involved in protein-protein and protein-DNA interactions. This protein was reported to interact with the tumor suppressor protein RB1. Studies of the rat counterpart suggested that this protein may function as an E3 ubiquitin-protein ligase, and facilitate the ubiquitination and degradation of syntaxin 1, which is an essential component of the neurotransmitter release machinery. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

RNF40 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18936825).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014771.4. 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
	RNF40	NM_014771.4	MANE Select	c.647G>C	p.Arg216Pro	missense splice_region	Exon 5 of 20	NP_055586.1	O75150-1
	RNF40	NM_001286572.3		c.647G>C	p.Arg216Pro	missense splice_region	Exon 5 of 20	NP_001273501.1	O75150-1
	RNF40	NM_001207033.1		c.647G>C	p.Arg216Pro	missense splice_region	Exon 5 of 20	NP_001193962.1	A8K6K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF40	ENST00000324685.11	TSL:1 MANE Select	c.647G>C	p.Arg216Pro	missense splice_region	Exon 5 of 20	ENSP00000325677.6	O75150-1
	RNF40	ENST00000946790.1		c.647G>C	p.Arg216Pro	missense splice_region	Exon 5 of 21	ENSP00000616849.1
	RNF40	ENST00000864896.1		c.647G>C	p.Arg216Pro	missense splice_region	Exon 4 of 19	ENSP00000534955.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.80	P
Vest4		0.39
MutPred		0.19		Loss of MoRF binding (P = 0.0067)
MVP		0.54
MPC		1.1
ClinPred		0.53	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.60
dbscSNV1_RF	Benign	0.55
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: rs564363255; hg19: chr16-30775704;