6-116877843-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173560.4(RFX6):c.271G>A(p.Asp91Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1453847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.271G>A	p.Asp91Asn	missense_variant	2/19	ENST00000332958.3
RFX6	XM_011535589.2	c.271G>A	p.Asp91Asn	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.271G>A	p.Asp91Asn	missense_variant	2/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.335G>A		non_coding_transcript_exon_variant	2/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 12, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RFX6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 91 of the RFX6 protein (p.Asp91Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.11
Sift	Uncertain	0.027	D
Sift4G	Benign	0.38	T
Polyphen		0.36	B
Vest4		0.23
MutPred		0.14		Gain of helix (P = 0.0696);
MVP		0.46
MPC		0.48
ClinPred		0.63	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-117199006;