rs267607012

chr6-116895184-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_173560.4(RFX6):c.649T>C(p.Ser217Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.68

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-116895184-T-C is Pathogenic according to our data. Variant chr6-116895184-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-116895184-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.649T>C	p.Ser217Pro	missense_variant	6/19	ENST00000332958.3
RFX6	XM_011535589.2	c.649T>C	p.Ser217Pro	missense_variant	6/18
RFX6	XM_017010477.2	c.271T>C	p.Ser91Pro	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.649T>C	p.Ser217Pro	missense_variant	6/19	1	NM_173560.4	P1
RFX6	ENST00000471966.1	n.340T>C		non_coding_transcript_exon_variant	3/7	5
RFX6	ENST00000487683.5	n.713T>C		non_coding_transcript_exon_variant	6/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1323984 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 665590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.017	D
Polyphen		0.80	P
Vest4		0.78
MutPred		0.36		Loss of phosphorylation at S217 (P = 0.0246);
MVP		0.65
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607012; hg19: chr6-117216347;