6-116877337-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_173560.4(RFX6):c.62C>A(p.Ser21Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,612,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.725

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018052548).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000545 (83/152318) while in subpopulation NFE AF= 0.000985 (67/68028). AF 95% confidence interval is 0.000795. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.62C>A	p.Ser21Tyr	missense_variant	1/19	ENST00000332958.3
RFX6	XM_011535589.2	c.62C>A	p.Ser21Tyr	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.62C>A	p.Ser21Tyr	missense_variant	1/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.126C>A		non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000582 AC: 143 AN: 245622 Hom.: 1 AF XY: 0.000583 AC XY: 78 AN XY: 133748

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1460554 Hom.: 1 Cov.: 32 AF XY: 0.000702 AC XY: 510 AN XY: 726498

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000823

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74474

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000998 Hom.: 2

Bravo AF: 0.000570

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000626 AC: 76

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 21 of the RFX6 protein (p.Ser21Tyr). This variant is present in population databases (rs146773792, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with RFX6-related conditions. ClinVar contains an entry for this variant (Variation ID: 917470). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 27, 2018

ACMG criteria: BP4 (REVEL score 0.081 + BP4 (9 predictors); not using PP3 (2 predictors)) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.081
Sift	Uncertain	0.0090	D
Sift4G	Benign	1.0	T
Polyphen		0.91	P
Vest4		0.39
MVP		0.34
MPC		0.99
ClinPred		0.025	T
GERP RS		5.3
Varity_R		0.094
gMVP		0.39

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: rs146773792; hg19: chr6-117198500;