rs9489056

chr6-116877325-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173560.4(RFX6):c.50C>A(p.Ala17Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,612,708 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (150 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (115 hom.)
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016258061).
• BP6: Variant 6-116877325-C-A is Benign according to our data. Variant chr6-116877325-C-A is described in ClinVar as [Benign]. Clinvar id is 130156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116877325-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.50C>A	p.Ala17Glu	missense_variant	1/19	ENST00000332958.3
RFX6	XM_011535589.2	c.50C>A	p.Ala17Glu	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.50C>A	p.Ala17Glu	missense_variant	1/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.114C>A		non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3737 AN: 152168 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00607 AC: 1490 AN: 245384 Hom.: 52 AF XY: 0.00440 AC XY: 589 AN XY: 133740

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00230 AC: 3364 AN: 1460422 Hom.: 115 Cov.: 32 AF XY: 0.00202 AC XY: 1469 AN XY: 726442

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.00444

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.0246 AC: 3751 AN: 152286 Hom.: 150 Cov.: 32 AF XY: 0.0240 AC XY: 1788 AN XY: 74478

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00807 Hom.: 39

Bravo AF: 0.0278

ESP6500AA AF: 0.0884 AC: 389

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00771 AC: 935

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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 0.078 + 9 predictors; not using PP3/2 predictors), BA1 (8.7% in gnomAD Africans), BS2 (84 homozygotes in gnomAD), BP1 (heterozygotes variants that cause MODY with reduced penetrance are LOF per PMID: 29026101)= 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

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.078
Sift	Uncertain	0.029	D
Sift4G	Benign	0.28	T
Polyphen		0.099	B
Vest4		0.28
MVP		0.24
MPC		0.64
ClinPred		0.011	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs9489056; hg19: chr6-117198488; COSMIC: COSV60583422;