rs187331767

Positions:

• chr19-19197255-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003721.4(RFXANK):​c.337+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,366 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (23 hom.)
• Consequence: RFXANK NM_003721.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0006120
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-19197255-C-T is Benign according to our data. Variant chr19-19197255-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 252622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00317 (482/152290) while in subpopulation AMR AF= 0.00497 (76/15286). AF 95% confidence interval is 0.00407. There are 6 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.337+4C>T		splice_donor_region_variant, intron_variant		ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.337+4C>T		splice_donor_region_variant, intron_variant		1	NM_003721.4	ENSP00000305071	P1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152172 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00411 AC: 1030 AN: 250430 Hom.: 4 AF XY: 0.00443 AC XY: 600 AN XY: 135484

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.000616

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00419 AC: 6119 AN: 1460076 Hom.: 23 Cov.: 32 AF XY: 0.00428 AC XY: 3109 AN XY: 726342

Gnomad4 AFR exome AF: 0.000748

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00413

Gnomad4 FIN exome AF: 0.000509

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152290 Hom.: 6 Cov.: 32 AF XY: 0.00299 AC XY: 223 AN XY: 74460

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.00332

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	RFXANK: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MHC class II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00061
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.070		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: rs187331767; hg19: chr19-19308064;