dbSNP rs339331: RFX6:c.567-5098T>C (chr6-116888889-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_173560.4(RFX6):c.567-5098T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 151,934 control chromosomes in the GnomAD database, including 6,395 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6395 hom., cov: 32)

Consequence

RFX6
NM_173560.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.74

Publications

130 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RFX6	NM_173560.4 link	c.567-5098T>C	intron_variant	Intron 4 of 18	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2 link	c.567-5098T>C	intron_variant	Intron 4 of 17		XP_011533891.1
RFX6	XM_017010477.2 link	c.189-5098T>C	intron_variant	Intron 3 of 17		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RFX6	ENST00000332958.3 link	c.567-5098T>C	intron_variant	Intron 4 of 18	1	NM_173560.4	ENSP00000332208.2
RFX6	ENST00000471966.1 link	n.257+3844T>C	intron_variant	Intron 1 of 6	5
RFX6	ENST00000487683.5 link	n.631-5098T>C	intron_variant	Intron 4 of 13	5

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43344

AN:

151816

Hom.:

6388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.250

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.286

AC:

43383

AN:

151934

Hom.:

6395

Cov.:

AF XY:

0.289

AC XY:

21453

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.238

AC:

9878

AN:

41478

American (AMR)

AF:

0.273

AC:

4169

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

411

AN:

3468

East Asian (EAS)

AF:

0.373

AC:

1928

AN:

5172

South Asian (SAS)

AF:

0.377

AC:

1815

AN:

4814

European-Finnish (FIN)

AF:

0.329

AC:

3471

AN:

10558

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.308

AC:

20903

AN:

67886

Other (OTH)

AF:

0.252

AC:

531

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1583

3166

4750

6333

7916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.294

Hom.:

29381

Bravo

AF:

0.275

Asia WGS

AF:

0.395

AC:

1374

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over