rs146081967

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173560.4(RFX6):c.2039C>A(p.Thr680Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,614,168 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T680A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

RFX6
NM_173560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.49

Publications

4 publications found

Variant links:

Genes affected

RFX6 (HGNC:21478): (regulatory factor X6) The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.[provided by RefSeq, Sep 2010]

RFX6 Gene-Disease associations (from GenCC):

Martinez-Frias syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Mitchell-Riley syndrome
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

RFX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01639241).

BP6

Variant 6-116927180-C-A is Benign according to our data. Variant chr6-116927180-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212052.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/152304) while in subpopulation NFE AF = 0.00207 (141/68022). AF 95% confidence interval is 0.00179. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RFX6	NM_173560.4 link	c.2039C>A	p.Thr680Lys	missense_variant	Exon 17 of 19	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2 link	c.1931C>A	p.Thr644Lys	missense_variant	Exon 16 of 18		XP_011533891.1
RFX6	XM_017010477.2 link	c.1661C>A	p.Thr554Lys	missense_variant	Exon 16 of 18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 link	c.2039C>A	p.Thr680Lys	missense_variant	Exon 17 of 19	1	NM_173560.4	ENSP00000332208.2

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00118

AC:

297

AN:

251374

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00186

AC:

2718

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1387

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00233

AC:

2592

AN:

1111986

Other (OTH)

AF:

0.000911

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

166

332

499

665

831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152304

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41580

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.000967

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00120

AC:

146

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in siblings with diabetes, one of whom had an additional variant in a different MODY-related gene in published literature (PMID: Pokrovskaya2022[CaseReport]); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Pokrovskaya2022[CaseReport]) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RFX6-related disorder

Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Monogenic diabetes

Benign:1

Sep 09, 2016

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: PP3, BP4, BP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

M_CAP

Benign

0.016

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PhyloP100

5.5

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.67

REVEL

Benign

0.072

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.036

Polyphen

0.12

Vest4

0.23

MVP

0.31

MPC

0.073

ClinPred

0.034

GERP RS

4.8

Varity_R

0.18

gMVP

0.34

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over