6-116925507-G-C

Position:

chr6-116925507-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173560.4(RFX6):c.1733G>C(p.Arg578Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,614,096 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 8 hom. )

Consequence

RFX6
NM_173560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 7.71

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0108983815).

BP6

Variant 6-116925507-G-C is Benign according to our data. Variant chr6-116925507-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436531.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr6-116925507-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00209 (319/152298) while in subpopulation AMR AF= 0.00366 (56/15286). AF 95% confidence interval is 0.0029. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RFX6	NM_173560.4 linkuse as main transcript	c.1733G>C	p.Arg578Pro	missense_variant	16/19	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2 linkuse as main transcript	c.1625G>C	p.Arg542Pro	missense_variant	15/18		XP_011533891.1
RFX6	XM_017010477.2 linkuse as main transcript	c.1355G>C	p.Arg452Pro	missense_variant	15/18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 linkuse as main transcript	c.1733G>C	p.Arg578Pro	missense_variant	16/19	1	NM_173560.4	ENSP00000332208	P1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00234

AC:

588

AN:

251160

Hom.:

AF XY:

0.00251

AC XY:

340

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00282

AC:

4125

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2054

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00326

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00209

AC:

319

AN:

152298

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00230

AC:

279

EpiCase

AF:

0.00409

EpiControl

AF:

0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RFX6: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	Feb 16, 2016	- -

RFX6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2020

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

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 02, 2018

ACMG criteria: PP3 (6 predictors), BP4 (4 predictors), BS2 (2 homozygotes in gnomAD and T2DM has 27 cases and 23 controls)=likely benign -

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.060

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.65

MVP

0.52

MPC

0.78

ClinPred

0.030

GERP RS

5.2

Varity_R

0.56

gMVP

0.73

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over