rs72997200

Variant names:

• chr19-19196988-C-T
• rs72997200
• NM_003721.4:c.213C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000303088.9(RFXANK):​c.213C>T​(p.Thr71Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,612,860 control chromosomes in the GnomAD database, including 3,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.046 (218 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3168 hom.)
• Consequence: RFXANK ENST00000303088.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.50
• Publications: 8 publications found

Genes affected

RFXANK (HGNC:9987): (regulatory factor X associated ankyrin containing protein) Major histocompatibility (MHC) class II molecules are transmembrane proteins that have a central role in development and control of the immune system. The protein encoded by this gene, along with regulatory factor X-associated protein and regulatory factor-5, forms a complex that binds to the X box motif of certain MHC class II gene promoters and activates their transcription. Once bound to the promoter, this complex associates with the non-DNA-binding factor MHC class II transactivator, which controls the cell type specificity and inducibility of MHC class II gene expression. This protein contains ankyrin repeats involved in protein-protein interactions. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group B. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2013]

RFXANK Gene-Disease associations (from GenCC):

• MHC class II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-19196988-C-T is Benign according to our data. Variant chr19-19196988-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328642.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000303088.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	NM_003721.4	MANE Select	c.213C>T	p.Thr71Thr	synonymous	Exon 4 of 10	NP_003712.1
	RFXANK	NM_001370238.1		c.213C>T	p.Thr71Thr	synonymous	Exon 3 of 10	NP_001357167.1
	RFXANK	NM_001370237.1		c.210C>T	p.Thr70Thr	synonymous	Exon 3 of 10	NP_001357166.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.213C>T	p.Thr71Thr	synonymous	Exon 4 of 10	ENSP00000305071.2
	RFXANK	ENST00000407360.7	TSL:1	c.213C>T	p.Thr71Thr	synonymous	Exon 3 of 9	ENSP00000384572.3
	RFXANK	ENST00000456252.7	TSL:1	c.213C>T	p.Thr71Thr	synonymous	Exon 4 of 9	ENSP00000409138.2

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 7001 AN: 152156 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0871

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0674

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0525 AC: 13109 AN: 249892 AF XY: 0.0551

Gnomad AFR exome AF: 0.00950

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.0888

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0686

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0628 AC: 91729 AN: 1460586 Hom.: 3168 Cov.: 33 AF XY: 0.0635 AC XY: 46151 AN XY: 726598

African (AFR) AF: 0.00989 AC: 331 AN: 33470

American (AMR) AF: 0.0334 AC: 1492 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 2293 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0532 AC: 4591 AN: 86256

European-Finnish (FIN) AF: 0.0583 AC: 3045 AN: 52246

Middle Eastern (MID) AF: 0.0723 AC: 417 AN: 5764

European-Non Finnish (NFE) AF: 0.0681 AC: 75724 AN: 1111916

Other (OTH) AF: 0.0634 AC: 3831 AN: 60384

GnomAD4 genome AF: 0.0460 AC: 6999 AN: 152274 Hom.: 218 Cov.: 32 AF XY: 0.0449 AC XY: 3342 AN XY: 74464

African (AFR) AF: 0.0112 AC: 466 AN: 41558

American (AMR) AF: 0.0462 AC: 706 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 302 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4830

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10610

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0674 AC: 4587 AN: 68010

Other (OTH) AF: 0.0540 AC: 114 AN: 2112

Alfa AF: 0.0569 Hom.: 241

Bravo AF: 0.0428

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0694

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	MHC class II deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.12
DANN	Benign	0.87
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs72997200; hg19: chr19-19307797; COSMIC: COSV107238770; COSMIC: COSV107238770;