NM_173560.4:c.2561C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_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. 15/22 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

Publications

7 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 -9 ACMG points.

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 submission is: [Conflicting_classifications_of_pathogenicity].

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX6	NM_173560.4 link	c.2561C>T	p.Ser854Leu	missense_variant	Exon 18 of 19	ENST00000332958.3	NP_775831.2	Q8HWS3
RFX6	XM_011535589.2 link	c.2453C>T	p.Ser818Leu	missense_variant	Exon 17 of 18		XP_011533891.1
RFX6	XM_017010477.2 link	c.2183C>T	p.Ser728Leu	missense_variant	Exon 17 of 18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 link	c.2561C>T	p.Ser854Leu	missense_variant	Exon 18 of 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

GnomAD2 exomes

AF:

0.000899

AC:

226

AN:

251414

AF XY:

0.000868

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.00203

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00364

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000836

AC:

929

AN:

1111508

Other (OTH)

AF:

0.000894

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000900

AC:

137

AN:

152268

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41568

American (AMR)

AF:

0.00203

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00106

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

Mar 31, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:PP3, BP4 -

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RFX6-related disorder

Benign:1

Feb 02, 2022

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). -

not provided

Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

4.3

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

Mutation Taster

=97/3

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