Genetic Variant NM_173560.4:c.649T>C (chr6-116895184-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.68

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
RFX6	NM_173560.4 link	c.649T>C	p.Ser217Pro	missense_variant	Exon 6 of 19	ENST00000332958.3	NP_775831.2	Q8HWS3
RFX6	XM_011535589.2 link	c.649T>C	p.Ser217Pro	missense_variant	Exon 6 of 18		XP_011533891.1
RFX6	XM_017010477.2 link	c.271T>C	p.Ser91Pro	missense_variant	Exon 5 of 18		XP_016865966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RFX6	ENST00000332958.3 link	c.649T>C	p.Ser217Pro	missense_variant	Exon 6 of 19	1	NM_173560.4	ENSP00000332208.2	Q8HWS3
RFX6	ENST00000471966.1 link	n.340T>C		non_coding_transcript_exon_variant	Exon 3 of 7	5
RFX6	ENST00000487683.5 link	n.713T>C		non_coding_transcript_exon_variant	Exon 6 of 14	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1323984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

Pathogenic:2

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.35

Sift

Uncertain

0.020

Sift4G

Uncertain

0.017

Polyphen

0.80

Vest4

0.78

MutPred

0.36

Loss of phosphorylation at S217 (P = 0.0246);

MVP

0.65

MPC

1.6

ClinPred

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over