6-116877498-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_173560.4(RFX6):c.223G>C(p.Glu75Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,553,608 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

RFX6
NM_173560.4 missense, splice_region

Scores

Splicing: ADA: 0.9941

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 3.54

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 -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 6-116877498-G-C is Benign according to our data. Variant chr6-116877498-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 702436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116877498-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152290) while in subpopulation NFE AF= 0.00153 (104/68012). AF 95% confidence interval is 0.00129. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX6	NM_173560.4 link	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	Exon 1 of 19	ENST00000332958.3	NP_775831.2	Q8HWS3
RFX6	XM_011535589.2 link	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	Exon 1 of 18		XP_011533891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 link	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	Exon 1 of 19	1	NM_173560.4	ENSP00000332208.2		Q8HWS3
RFX6	ENST00000487683.5 link	n.287G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00139

AC:

218

AN:

156656

Hom.:

AF XY:

0.00145

AC XY:

121

AN XY:

83556

show subpopulations

Gnomad AFR exome

AF:

0.000254

Gnomad AMR exome

AF:

0.000836

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000171

Gnomad SAS exome

AF:

0.00153

Gnomad FIN exome

AF:

0.00390

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.00132

AC:

1846

AN:

1401318

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

924

AN XY:

691468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000314

Gnomad4 AMR exome

AF:

0.000993

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000331

Gnomad4 SAS exome

AF:

0.00171

Gnomad4 FIN exome

AF:

0.00389

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.00138

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152290

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.000945

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000718

AC:

ExAC

AF:

0.000781

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RFX6-related disorder

Benign:1

Jan 28, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.087

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.81

REVEL

Benign

0.089

Sift

Benign

0.059

Sift4G

Benign

0.18

Polyphen

0.18

Vest4

0.26

MVP

0.62

MPC

0.53

ClinPred

0.066

GERP RS

4.6

Varity_R

0.23

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

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

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