chr6-116911037-GACAAGGTATCAATT-G

Position:

• chr6-116911037-GACAAGGTATCAATT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP3 PP5

The NM_173560.4(RFX6):​c.779_780+12del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX6 NM_173560.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.52

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038392536 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-116911037-GACAAGGTATCAATT-G is Pathogenic according to our data. Variant chr6-116911037-GACAAGGTATCAATT-G is described in ClinVar as [Pathogenic]. Clinvar id is 501.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.779_780+12del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/19	ENST00000332958.3
RFX6	XM_011535589.2	c.673-4967_673-4954del		intron_variant
RFX6	XM_017010477.2	c.401_402+12del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.779_780+12del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/19	1	NM_173560.4	P1
RFX6	ENST00000471966.1	n.470_471+12del		splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	4/7	5
RFX6	ENST00000487683.5	n.843_844+12del		splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	7/14	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 11, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776517; hg19: chr6-117232200;