6-116877485-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_173560.4(RFX6):c.210G>A(p.Gly70=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,558,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: RFX6 NM_173560.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0600

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-116877485-G-A is Benign according to our data. Variant chr6-116877485-G-A is described in ClinVar as [Benign]. Clinvar id is 1170402.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-116877485-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000381 (58/152332) while in subpopulation SAS AF= 0.00145 (7/4832). AF 95% confidence interval is 0.000679. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX6	NM_173560.4	c.210G>A	p.Gly70=	synonymous_variant	1/19	ENST00000332958.3
RFX6	XM_011535589.2	c.210G>A	p.Gly70=	synonymous_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX6	ENST00000332958.3	c.210G>A	p.Gly70=	synonymous_variant	1/19	1	NM_173560.4	P1
RFX6	ENST00000487683.5	n.274G>A		non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000674 AC: 109 AN: 161708 Hom.: 0 AF XY: 0.000776 AC XY: 67 AN XY: 86304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000831

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.000400 AC: 563 AN: 1406340 Hom.: 1 Cov.: 32 AF XY: 0.000452 AC XY: 314 AN XY: 694212

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000242

Gnomad4 OTH exome AF: 0.000737

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000446

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.8
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs371479688; hg19: chr6-117198648;