rs1364016225

Variant names:

• chr6-116877483-G-A
• rs1364016225
• NM_173560.4:c.208G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-116877483-G-A
• chr6-116877483-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173560.4(RFX6):​c.208G>A​(p.Gly70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. G70V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RFX6 NM_173560.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• 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):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Martinez-Frias syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Mitchell-Riley syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08313811).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	NM_173560.4	MANE Select	c.208G>A	p.Gly70Arg	missense	Exon 1 of 19	NP_775831.2	Q8HWS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX6	ENST00000332958.3	TSL:1 MANE Select	c.208G>A	p.Gly70Arg	missense	Exon 1 of 19	ENSP00000332208.2	Q8HWS3
	RFX6	ENST00000487683.5	TSL:5	n.272G>A		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 162314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1406936 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694552

African (AFR) AF: 0.0000624 AC: 2 AN: 32034

American (AMR) AF: 0.00 AC: 0 AN: 36898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36522

South Asian (SAS) AF: 0.00 AC: 0 AN: 79770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083094

Other (OTH) AF: 0.00 AC: 0 AN: 58364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.0
DANN	Benign	0.89
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.061
Sift	Benign	0.12	T
Sift4G	Benign	0.60	T
Polyphen		0.055	B
Vest4		0.18
MutPred		0.14		Gain of helix (P = 0.0117)
MVP		0.36
MPC		0.61
ClinPred		0.17	T
GERP RS		4.3
PromoterAI		0.026	Neutral
Varity_R		0.051
gMVP		0.24
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1364016225; hg19: chr6-117198646;