rs182606018

Positions:

• chr6-116922032-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173560.4(RFX6):​c.1328-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,157,496 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 31)
  • Exomes 𝑓: 0.018 (180 hom.)
• Consequence: RFX6 NM_173560.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001042
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0370

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 (BayesDel_noAF=-0.76).
• BP6: Variant 6-116922032-T-C is Benign according to our data. Variant chr6-116922032-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116922032-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0161 (2438/151558) while in subpopulation NFE AF= 0.0263 (1785/67806). AF 95% confidence interval is 0.0253. There are 26 homozygotes in gnomad4. There are 1075 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX6	NM_173560.4	c.1328-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2	c.1220-10T>C		splice_polypyrimidine_tract_variant, intron_variant			XP_011533891.1
RFX6	XM_017010477.2	c.950-10T>C		splice_polypyrimidine_tract_variant, intron_variant			XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3	c.1328-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_173560.4	ENSP00000332208	P1
RFX6	ENST00000487683.5	n.1392-10T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2438 AN: 151438 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0158 AC: 3771 AN: 238422 Hom.: 31 AF XY: 0.0161 AC XY: 2087 AN XY: 129360

Gnomad AFR exome AF: 0.00467

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0000583

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00371

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0182 AC: 18261 AN: 1005938 Hom.: 180 Cov.: 14 AF XY: 0.0179 AC XY: 9326 AN XY: 520798

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0161 AC: 2438 AN: 151558 Hom.: 26 Cov.: 31 AF XY: 0.0145 AC XY: 1075 AN XY: 74110

Gnomad4 AFR AF: 0.00502

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00376

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0183 Hom.: 10

Bravo AF: 0.0173

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 27, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.24
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.076
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: rs182606018; hg19: chr6-117243195;