6-116877498-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS1

The NM_173560.4(RFX6):c.223G>C(p.Glu75Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,553,608 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: RFX6 NM_173560.4 missense, splice_region
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 3.54

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 -11 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-116877498-G-C is Benign according to our data. Variant chr6-116877498-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 702436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116877498-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152290) while in subpopulation NFE AF= 0.00153 (104/68012). AF 95% confidence interval is 0.00129. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	1/19	ENST00000332958.3
RFX6	XM_011535589.2	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.223G>C	p.Glu75Gln	missense_variant, splice_region_variant	1/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.287G>C		splice_region_variant, non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00139 AC: 218 AN: 156656 Hom.: 1 AF XY: 0.00145 AC XY: 121 AN XY: 83556

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000836

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000171

Gnomad SAS exome AF: 0.00153

Gnomad FIN exome AF: 0.00390

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00132 AC: 1846 AN: 1401318 Hom.: 2 Cov.: 31 AF XY: 0.00134 AC XY: 924 AN XY: 691468

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.000993

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000331

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.00389

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74456

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.000945

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000718 AC: 6

ExAC AF: 0.000781 AC: 87

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

RFX6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.089
Sift	Benign	0.059	T
Sift4G	Benign	0.18	T
Polyphen		0.18	B
Vest4		0.26
MVP		0.62
MPC		0.53
ClinPred		0.066	T
GERP RS		4.6
Varity_R		0.23
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs201996097; hg19: chr6-117198661;