NM_173560.4:c.1328-10T>C

Variant names:

• chr6-116922032-T-C
• rs182606018
• NM_173560.4:c.1328-10T>C

Variant summary

Our verdict is Benign. The variant received -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 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 intron
• Scores: Splicing: ADA: 0.001042
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0370
• Publications: 0 publications found

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]

RFX6 Gene-Disease associations (from GenCC):

• Martinez-Frias syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Mitchell-Riley syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 130149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	NM_173560.4	MANE Select	c.1328-10T>C		intron	N/A	NP_775831.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	ENST00000332958.3	TSL:1 MANE Select	c.1328-10T>C		intron	N/A	ENSP00000332208.2
	RFX6	ENST00000487683.5	TSL:5	n.1392-10T>C		intron	N/A

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

GnomAD2 exomes AF: 0.0158 AC: 3771 AN: 238422 AF XY: 0.0161

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 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

African (AFR) AF: 0.00356 AC: 85 AN: 23886

American (AMR) AF: 0.0112 AC: 470 AN: 42008

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 541 AN: 23112

East Asian (EAS) AF: 0.00 AC: 0 AN: 37586

South Asian (SAS) AF: 0.00145 AC: 108 AN: 74688

European-Finnish (FIN) AF: 0.00402 AC: 199 AN: 49452

Middle Eastern (MID) AF: 0.0190 AC: 92 AN: 4836

European-Non Finnish (NFE) AF: 0.0226 AC: 15943 AN: 705380

Other (OTH) AF: 0.0183 AC: 823 AN: 44990

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

African (AFR) AF: 0.00502 AC: 208 AN: 41412

American (AMR) AF: 0.0178 AC: 271 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4794

European-Finnish (FIN) AF: 0.00376 AC: 39 AN: 10376

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1785 AN: 67806

Other (OTH) AF: 0.0152 AC: 32 AN: 2100

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

Apr 07, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.24
DANN	Benign	0.81
PhyloP100		0.037
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs182606018; hg19: chr6-117243195;