6-116920454-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173560.4(RFX6):c.1327C>T(p.His443Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,612,210 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H443R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 32 hom. )

Consequence

RFX6
NM_173560.4 missense, splice_region

Scores

Splicing: ADA: 0.0003669

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.10

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025072992).

BP6

Variant 6-116920454-C-T is Benign according to our data. Variant chr6-116920454-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2139/152236) while in subpopulation AFR AF = 0.049 (2036/41530). AF 95% confidence interval is 0.0473. There are 48 homozygotes in GnomAd4. There are 1007 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RFX6	NM_173560.4 link	c.1327C>T	p.His443Tyr	missense_variant, splice_region_variant	Exon 12 of 19	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2 link	c.1219C>T	p.His407Tyr	missense_variant, splice_region_variant	Exon 11 of 18		XP_011533891.1
RFX6	XM_017010477.2 link	c.949C>T	p.His317Tyr	missense_variant, splice_region_variant	Exon 11 of 18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 link	c.1327C>T	p.His443Tyr	missense_variant, splice_region_variant	Exon 12 of 19	1	NM_173560.4	ENSP00000332208.2
RFX6	ENST00000487683.5 link	n.1391C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2127

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00492

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00370

AC:

929

AN:

251194

AF XY:

0.00283

show subpopulations

Gnomad AFR exome

AF:

0.0501

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00127

AC:

1854

AN:

1459974

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

860

AN XY:

726448

show subpopulations

African (AFR)

AF:

0.0437

AC:

1459

AN:

33404

American (AMR)

AF:

0.00244

AC:

109

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.000101

AC:

AN:

39666

South Asian (SAS)

AF:

0.000731

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1110372

Other (OTH)

AF:

0.00307

AC:

185

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0141

AC:

2139

AN:

152236

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1007

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0490

AC:

2036

AN:

41530

American (AMR)

AF:

0.00491

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68018

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00532

Hom.:

Bravo

AF:

0.0155

ESP6500AA

AF:

0.0504

AC:

222

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00464

AC:

563

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Dec 21, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BP4 (REVEL 0.132 + 9 predictors), BA1 (4.9% MAF in gnomAD Africans), BS2 (31 homozygotes in gnomAD)=Benign -

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

Benign:1

Sep 13, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.078

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.76

M_CAP

Benign

0.0091

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

PhyloP100

1.1

PrimateAI

Benign

0.48

PROVEAN

Benign

0.060

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.19

MVP

0.17

MPC

0.57

ClinPred

0.0068

GERP RS

-3.7

Varity_R

0.039

gMVP

0.12

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.020

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