rs587776517

Variant names:

• chr6-116911037-GACAAGGTATCAATT-G
• rs587776517
• NM_173560.4:c.779_780+12delAGGTATCAATTACA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_173560.4(RFX6):​c.779_780+12delAGGTATCAATTACA​(p.Lys260AlafsTer18) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX6 NM_173560.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.52
• 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):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Martinez-Frias syndrome

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

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-116911037-GACAAGGTATCAATT-G is Pathogenic according to our data. Variant chr6-116911037-GACAAGGTATCAATT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 501.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	NM_173560.4	MANE Select	c.779_780+12delAGGTATCAATTACA	p.Lys260AlafsTer18	frameshift splice_donor splice_region intron	Exon 7 of 19	NP_775831.2	Q8HWS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	ENST00000332958.3	TSL:1 MANE Select	c.776_780+9delACAAGGTATCAATT	p.Asp259AlafsTer18	frameshift splice_donor splice_region intron	Exon 7 of 19	ENSP00000332208.2	Q8HWS3
	RFX6	ENST00000471966.1	TSL:5	n.467_471+9delACAAGGTATCAATT		splice_donor splice_region intron non_coding_transcript_exon	Exon 4 of 7
	RFX6	ENST00000487683.5	TSL:5	n.840_844+9delACAAGGTATCAATT		splice_donor splice_region intron non_coding_transcript_exon	Exon 7 of 14

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776517; hg19: chr6-117232200;