chr6-116913548-T-C

Variant names:

• chr6-116913548-T-C
• rs9489065
• NM_173560.4:c.781-2460T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173560.4(RFX6):​c.781-2460T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 152,090 control chromosomes in the GnomAD database, including 6,801 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6801 hom., cov: 32)
• Consequence: RFX6 NM_173560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX6	NM_173560.4	c.781-2460T>C		intron_variant	Intron 7 of 18	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2	c.673-2460T>C		intron_variant	Intron 6 of 17		XP_011533891.1
RFX6	XM_017010477.2	c.403-2460T>C		intron_variant	Intron 6 of 17		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3	c.781-2460T>C		intron_variant	Intron 7 of 18	1	NM_173560.4	ENSP00000332208.2
RFX6	ENST00000471966.1	n.472-2460T>C		intron_variant	Intron 4 of 6	5
RFX6	ENST00000487683.5	n.845-2460T>C		intron_variant	Intron 7 of 13	5

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44822 AN: 151972 Hom.: 6792 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.295 AC: 44866 AN: 152090 Hom.: 6801 Cov.: 32 AF XY: 0.299 AC XY: 22199 AN XY: 74342

African (AFR) AF: 0.267 AC: 11084 AN: 41498

American (AMR) AF: 0.276 AC: 4216 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 411 AN: 3470

East Asian (EAS) AF: 0.378 AC: 1953 AN: 5164

South Asian (SAS) AF: 0.403 AC: 1943 AN: 4822

European-Finnish (FIN) AF: 0.331 AC: 3493 AN: 10566

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20943 AN: 67984

Other (OTH) AF: 0.257 AC: 543 AN: 2110

Alfa AF: 0.275 Hom.: 2813

Bravo AF: 0.285

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.41
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9489065; hg19: chr6-117234711;