rs187331767

Variant names:

• chr19-19197255-C-T
• rs187331767
• NM_003721.4:c.337+4C>T

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0006120
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.28
• Publications: 2 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.337+4C>T		splice_region_variant, intron_variant	Intron 5 of 9	ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.337+4C>T		splice_region_variant, intron_variant	Intron 5 of 9	1	NM_003721.4	ENSP00000305071.2

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

GnomAD2 exomes AF: 0.00411 AC: 1030 AN: 250430 AF XY: 0.00443

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 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

African (AFR) AF: 0.000748 AC: 25 AN: 33438

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 359 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00413 AC: 356 AN: 86188

European-Finnish (FIN) AF: 0.000509 AC: 27 AN: 53028

Middle Eastern (MID) AF: 0.0196 AC: 92 AN: 4698

European-Non Finnish (NFE) AF: 0.00432 AC: 4799 AN: 1111892

Other (OTH) AF: 0.00445 AC: 268 AN: 60278

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

African (AFR) AF: 0.000842 AC: 35 AN: 41576

American (AMR) AF: 0.00497 AC: 76 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68022

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RFXANK: BP4, BS2 -

not specified Benign:1

Sep 28, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MHC class II deficiency Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		-1.3
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs187331767; hg19: chr19-19308064;