rs182606018

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.1328-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,157,496 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 26 hom., cov: 31)

Exomes 𝑓: 0.018 ( 180 hom. )

Consequence

RFX6
NM_173560.4 intron

Scores

Splicing: ADA: 0.001042

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0370

Publications

0 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 (BayesDel_noAF=-0.76).

BP6

Variant 6-116922032-T-C is Benign according to our data. Variant chr6-116922032-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2438/151558) while in subpopulation NFE AF = 0.0263 (1785/67806). AF 95% confidence interval is 0.0253. There are 26 homozygotes in GnomAd4. There are 1075 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RFX6	NM_173560.4 link	c.1328-10T>C	intron_variant	Intron 12 of 18	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2 link	c.1220-10T>C	intron_variant	Intron 11 of 17		XP_011533891.1
RFX6	XM_017010477.2 link	c.950-10T>C	intron_variant	Intron 11 of 17		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 link	c.1328-10T>C		intron_variant	Intron 12 of 18	1	NM_173560.4	ENSP00000332208.2
RFX6	ENST00000487683.5 link	n.1392-10T>C		intron_variant	Intron 12 of 13	5

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2438

AN:

151438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00504

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.00376

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0263

Gnomad OTH

AF:

0.0154

GnomAD2 exomes

AF:

0.0158

AC:

3771

AN:

238422

AF XY:

0.0161

show subpopulations

Gnomad AFR exome

AF:

0.00467

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0232

Gnomad EAS exome

AF:

0.0000583

Gnomad FIN exome

AF:

0.00371

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0182

AC:

18261

AN:

1005938

Hom.:

180

Cov.:

AF XY:

0.0179

AC XY:

9326

AN XY:

520798

show subpopulations

African (AFR)

AF:

0.00356

AC:

AN:

23886

American (AMR)

AF:

0.0112

AC:

470

AN:

42008

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

541

AN:

23112

East Asian (EAS)

AF:

0.00

AC:

AN:

37586

South Asian (SAS)

AF:

0.00145

AC:

108

AN:

74688

European-Finnish (FIN)

AF:

0.00402

AC:

199

AN:

49452

Middle Eastern (MID)

AF:

0.0190

AC:

AN:

4836

European-Non Finnish (NFE)

AF:

0.0226

AC:

15943

AN:

705380

Other (OTH)

AF:

0.0183

AC:

823

AN:

44990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

695

1389

2084

2778

3473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.0161

AC:

2438

AN:

151558

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1075

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.00502

AC:

208

AN:

41412

American (AMR)

AF:

0.0178

AC:

271

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00229

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00376

AC:

AN:

10376

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0263

AC:

1785

AN:

67806

Other (OTH)

AF:

0.0152

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

113

226

338

451

564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0183

Hom.:

Bravo

AF:

0.0173

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.24

(source)

DANN

Benign

0.81

PhyloP100

0.037

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0010

dbscSNV1_RF

Benign

0.076

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