rs201522681

Positions:

chr6-116928921-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_173560.4(RFX6):c.2561C>T(p.Ser854Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000829 in 1,613,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

RFX6
NM_173560.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.31

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0096152425).

BP6

Variant 6-116928921-C-T is Benign according to our data. Variant chr6-116928921-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393396.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr6-116928921-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0009 (137/152268) while in subpopulation AMR AF= 0.00203 (31/15282). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX6	NM_173560.4 linkuse as main transcript	c.2561C>T	p.Ser854Leu	missense_variant	18/19	ENST00000332958.3	NP_775831.2	Q8HWS3
RFX6	XM_011535589.2 linkuse as main transcript	c.2453C>T	p.Ser818Leu	missense_variant	17/18		XP_011533891.1
RFX6	XM_017010477.2 linkuse as main transcript	c.2183C>T	p.Ser728Leu	missense_variant	17/18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 linkuse as main transcript	c.2561C>T	p.Ser854Leu	missense_variant	18/19	1	NM_173560.4	ENSP00000332208.2		Q8HWS3

Frequencies

GnomAD3 genomes

AF:

0.000900

AC:

137

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000899

AC:

226

AN:

251414

Hom.:

AF XY:

0.000868

AC XY:

118

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.000765

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.000822

AC:

1201

AN:

1461320

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

582

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.000836

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152268

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000786

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 31, 2017

ACMG Criteria:PP3, BP4 -

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

RFX6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2022

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0096

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

REVEL

Benign

0.062

Sift

Uncertain

0.028

Sift4G

Uncertain

0.045

Polyphen

0.013

Vest4

0.45

MVP

0.22

MPC

0.051

ClinPred

0.038

GERP RS

4.8

Varity_R

0.14

gMVP

0.33

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

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