NM_014771.4:c.703C>G

Variant names:

• chr16-30764991-C-G
• rs754279522
• NM_014771.4:c.703C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014771.4(RNF40):​c.703C>G​(p.Arg235Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,520 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. 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. R235H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNF40 NM_014771.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1388475).
• BS2: High AC in GnomAd4 at 13 AD gene.

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.703C>G	p.Arg235Gly	missense	Exon 6 of 20	NP_055586.1	O75150-1
	RNF40	NM_001286572.3		c.703C>G	p.Arg235Gly	missense	Exon 6 of 20	NP_001273501.1	O75150-1
	RNF40	NM_001207033.1		c.703C>G	p.Arg235Gly	missense	Exon 6 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.703C>G	p.Arg235Gly	missense	Exon 6 of 20	ENSP00000325677.6	O75150-1
	RNF40	ENST00000946790.1		c.766C>G	p.Arg256Gly	missense	Exon 7 of 21	ENSP00000616849.1
	RNF40	ENST00000864896.1		c.703C>G	p.Arg235Gly	missense	Exon 5 of 19	ENSP00000534955.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461238 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

African (AFR) AF: 0.000313 AC: 13 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.078
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PhyloP100		2.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.29	T
Polyphen		0.0030	B
Vest4		0.50
MVP		0.72
MPC		0.74
ClinPred		0.40	T
GERP RS		3.8
Varity_R		0.20
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754279522; hg19: chr16-30776312;