3-149872041-A-G

Position:

• chr3-149872041-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000392894.8(RNF13):​c.208A>G​(p.Asn70Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RNF13 ENST00000392894.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

Genes affected

RNF13 (HGNC:10057): (ring finger protein 13) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. The specific function of this gene has not yet been determined. Alternatively spliced transcript variants that encode the same protein have been reported. A pseudogene, which is also located on chromosome 3, has been defined for this gene. [provided by RefSeq, Jul 2008]

ANKUB1 (HGNC:29642): (ankyrin repeat and ubiquitin domain containing 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2822601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF13	NM_183381.3	c.208A>G	p.Asn70Asp	missense_variant	4/10	ENST00000392894.8	NP_899237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF13	ENST00000392894.8	c.208A>G	p.Asn70Asp	missense_variant	4/10	1	NM_183381.3	ENSP00000376628	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436096 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 714064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.208A>G (p.N70D) alteration is located in exon 5 (coding exon 3) of the RNF13 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the asparagine (N) at amino acid position 70 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0041	T;T;.;T;.;.;T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	.;T;T;D;T;T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.;.
MutationTaster	Benign	0.62	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.060	N;N;N;N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.61	T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T
Polyphen		0.13	B;B;.;.;.;.;.;.
Vest4		0.59
MutPred		0.42		Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);Gain of catalytic residue at N70 (P = 0.0868);
MVP		0.58
MPC		0.23
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1712130287; hg19: chr3-149589828;