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):

• 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX6	NM_173560.4	c.779_780+12delAGGTATCAATTACA	p.Lys260AlafsTer18	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 7 of 19	ENST00000332958.3	NP_775831.2
RFX6	XM_011535589.2	c.673-4967_673-4954delAGGTATCAATTACA		intron_variant	Intron 6 of 17		XP_011533891.1
RFX6	XM_017010477.2	c.401_402+12delAGGTATCAATTACA	p.Lys134AlafsTer18	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX6	ENST00000332958.3	c.776_780+9delACAAGGTATCAATT	p.Asp259AlafsTer18	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 7 of 19	1	NM_173560.4	ENSP00000332208.2
RFX6	ENST00000471966.1	n.467_471+9delACAAGGTATCAATT		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 4 of 7	5
RFX6	ENST00000487683.5	n.840_844+9delACAAGGTATCAATT		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 7 of 14	5

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome Pathogenic:1

Feb 11, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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;