12-120546464-A-C

Variant names:

• chr12-120546464-A-C
• rs757634356
• NM_014868.5:c.217A>C
• RNF10 p.Lys73Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_014868.5(RNF10):c.217A>C (p.Lys73Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000205 (AC=3) in the gnomAD database across 1,461,774 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000072. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.52). Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNF10 NM_014868.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.52
• Publications: 0 publications found

Genes affected

RNF10 (HGNC:10055): (ring finger protein 10) The protein encoded by this gene contains a ring finger motif, which is known to be involved in protein-protein interactions. The specific function of this protein has not yet been determined. EST data suggests the existence of multiple alternatively spliced transcript variants, however, their full length nature is not known. [provided by RefSeq, Jul 2008]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000072 — very rare for unknown gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014868.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF10 NM_014868.5	MANE Select	c.217A>C p.Lys73Gln	missense	Exon 2 of 17	Prot: NP_055683.3
	RNF10 NM_001330474.2		c.217A>C p.Lys73Gln	missense	Exon 2 of 17	Prot: NP_001317403.1 UniProt:

RNF10 NM_014868.5

MANE Select

HGVSc / HGVSpc.217A>Cp.Lys73Gln

Exon rankExon 2 of 17

missense

Prot: NP_055683.3

RNF10 NM_001330474.2

HGVSc / HGVSpc.217A>Cp.Lys73Gln

Exon rankExon 2 of 17

missense

Prot: NP_001317403.1UniProt: Q8N5U6-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF10 ENST00000325954.9	TSL:1MANE Select	c.217A>C p.Lys73Gln	missense	Exon 2 of 17	Prot: ENSP00000322242.4 UniProt:
	RNF10 ENST00000413266.6	TSL:5	c.217A>C p.Lys73Gln	missense	Exon 2 of 17	Prot: ENSP00000415682.2 UniProt:
	RNF10 ENST00000537997.1	TSL:4	c.67A>C p.Lys23Gln	missense	Exon 3 of 4	Prot: ENSP00000443235.1 UniProt:

RNF10 ENST00000325954.9

TSL:1MANE Select

HGVSc / HGVSpc.217A>Cp.Lys73Gln

Exon rankExon 2 of 17

missense

Prot: ENSP00000322242.4UniProt: Q8N5U6-1

RNF10 ENST00000413266.6

TSL:5

HGVSc / HGVSpc.217A>Cp.Lys73Gln

Exon rankExon 2 of 17

missense

Prot: ENSP00000415682.2UniProt: Q8N5U6-2

RNF10 ENST00000537997.1

TSL:4

HGVSc / HGVSpc.67A>Cp.Lys23Gln

Exon rankExon 3 of 4

missense

Prot: ENSP00000443235.1UniProt: F5H5P6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251360	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461774	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:36228	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000207	1	48352	0.0000134	1	74410

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Benign	0.067
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.44	D
Mutation Taster	N/A	77/23	polymorphism
MutationAssessor	Uncertain	2.5	M
PhyloP100	Pathogenic	8.5
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.52
Sift	Uncertain	0.028	D
Sift4G	Benign	0.14	T
Varity_R	N/A	0.35
VESM-3B	Benign	-4.3

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs757634356;

hg19: chr12-120984267;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar