rs72997200

Positions:

• chr19-19196988-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003721.4(RFXANK):​c.213C>T​(p.Thr71=) 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 NM_003721.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.50

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 328642.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.213C>T	p.Thr71=	synonymous_variant	4/10	ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.213C>T	p.Thr71=	synonymous_variant	4/10	1	NM_003721.4	ENSP00000305071	P1

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

GnomAD3 exomes AF: 0.0525 AC: 13109 AN: 249892 Hom.: 428 AF XY: 0.0551 AC XY: 7453 AN XY: 135178

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 SAS exome AF: 0.0519

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

Gnomad4 AFR exome AF: 0.00989

Gnomad4 AMR exome AF: 0.0334

Gnomad4 ASJ exome AF: 0.0877

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0532

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0681

Gnomad4 OTH exome AF: 0.0634

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

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0462

Gnomad4 ASJ AF: 0.0871

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0466

Gnomad4 FIN AF: 0.0525

Gnomad4 NFE AF: 0.0674

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0617 Hom.: 110

Bravo AF: 0.0428

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0694

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MHC class II deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.12
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs72997200; hg19: chr19-19307797;