rs267607013

chr6-116882404-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_173560.4(RFX6):c.542G>A(p.Arg181Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.72

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a DNA_binding_region RFX-type winged-helix (size 75) in uniprot entity RFX6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_173560.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-116882403-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 130157.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 6-116882404-G-A is Pathogenic according to our data. Variant chr6-116882404-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-116882404-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.542G>A	p.Arg181Gln	missense_variant	4/19	ENST00000332958.3
RFX6	XM_011535589.2	c.542G>A	p.Arg181Gln	missense_variant	4/18
RFX6	XM_017010477.2	c.164G>A	p.Arg55Gln	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.542G>A	p.Arg181Gln	missense_variant	4/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.606G>A		non_coding_transcript_exon_variant	4/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726634

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

RFX6-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

The RFX6 c.542G>A variant is predicted to result in the amino acid substitution p.Arg181Gln. This variant was reported in the homozygous state in an individual with neonatal diabetes and intestinal atresia (Smith et al 2010. PubMed ID: 20148032; Martinovici et al 2010. PubMed ID: 19887127). In vivo experimental studies suggest this variant impacts protein function (Pearl et al 2011. PubMed ID: 21215266). An alternative nucleotide change affecting the same amino acid (p.Arg181Trp) has been reported in the homozygous state in multiple individuals with Mitchell-Riley syndrome (Amorim et al. 2015. PubMed ID: 26770845; Passone et al. 2022. PubMed ID: 35813646). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as likely pathogenic. -

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 11, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.84		Loss of methylation at R181 (P = 0.0288);
MVP		0.64
MPC		1.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs267607013; hg19: chr6-117203567;