chr6-116920454-C-T

Position:

chr6-116920454-C-T

Variant summary

Our verdict is Benign. Variant got -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. 18/23 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 (★★).

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

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:

RFX6 (HGNC:):

RFX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 130148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116920454-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX6	NM_173560.4 linkuse as main transcript	c.1327C>T	p.His443Tyr	missense_variant, splice_region_variant	12/19	ENST00000332958.3	NP_775831.2	Q8HWS3
RFX6	XM_011535589.2 linkuse as main transcript	c.1219C>T	p.His407Tyr	missense_variant, splice_region_variant	11/18		XP_011533891.1
RFX6	XM_017010477.2 linkuse as main transcript	c.949C>T	p.His317Tyr	missense_variant, splice_region_variant	11/18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3 linkuse as main transcript	c.1327C>T	p.His443Tyr	missense_variant, splice_region_variant	12/19	1	NM_173560.4	ENSP00000332208.2		Q8HWS3
RFX6	ENST00000487683.5 linkuse as main transcript	n.1391C>T		splice_region_variant, non_coding_transcript_exon_variant	12/14	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

GnomAD3 exomes

AF:

0.00370

AC:

929

AN:

251194

Hom.:

AF XY:

0.00283

AC XY:

384

AN XY:

135752

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 SAS exome

AF:

0.000490

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

Gnomad4 AFR exome

AF:

0.0437

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00307

GnomAD4 genome

AF:

0.0141

AC:

2139

AN:

152236

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1007

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0490

Gnomad4 AMR

AF:

0.00491

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00199

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2013

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 21, 2018

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2021

- -

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

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

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

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

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