6-116877440-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_173560.4(RFX6):c.165C>T(p.Gly55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,587,382 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: RFX6 NM_173560.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0470

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-116877440-C-T is Benign according to our data. Variant chr6-116877440-C-T is described in ClinVar as [Benign]. Clinvar id is 1336023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.047 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000434 (66/152244) while in subpopulation SAS AF= 0.000622 (3/4826). AF 95% confidence interval is 0.00023. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.165C>T	p.Gly55=	synonymous_variant	1/19	ENST00000332958.3
RFX6	XM_011535589.2	c.165C>T	p.Gly55=	synonymous_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.165C>T	p.Gly55=	synonymous_variant	1/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.229C>T		non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000714 AC: 144 AN: 201808 Hom.: 2 AF XY: 0.000635 AC XY: 69 AN XY: 108736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000668

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.0000661

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.000959

GnomAD4 exome AF: 0.000407 AC: 584 AN: 1435138 Hom.: 2 Cov.: 32 AF XY: 0.000405 AC XY: 288 AN XY: 711012

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.0000731

Gnomad4 ASJ exome AF: 0.00914

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000390

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.000792

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74426

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000869 Hom.: 1

Bravo AF: 0.000442

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 24, 2021

- -

RFX6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.2
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs368072920; hg19: chr6-117198603;