19-19199238-A-G

Variant names:

• chr19-19199238-A-G
• rs73922830
• NM_003721.4:c.712+4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003721.4(RFXANK):​c.712+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,614,024 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (208 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (198 hom.)
• Consequence: RFXANK NM_003721.4 splice_region, intron
• Scores: Splicing: ADA: 0.03724
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.203
• Publications: 1 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=-0.9).
• BP6: Variant 19-19199238-A-G is Benign according to our data. Variant chr19-19199238-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003721.4. 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.712+4A>G		splice_region intron	N/A	NP_003712.1
	RFXANK	NM_001370238.1		c.712+4A>G		splice_region intron	N/A	NP_001357167.1
	RFXANK	NM_001370237.1		c.709+4A>G		splice_region intron	N/A	NP_001357166.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.712+4A>G		splice_region intron	N/A	ENSP00000305071.2
	RFXANK	ENST00000407360.7	TSL:1	c.712+4A>G		splice_region intron	N/A	ENSP00000384572.3
	RFXANK	ENST00000456252.7	TSL:1	c.646+4A>G		splice_region intron	N/A	ENSP00000409138.2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4286 AN: 152172 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00773 AC: 1940 AN: 251104 AF XY: 0.00568

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00306 AC: 4473 AN: 1461734 Hom.: 198 Cov.: 32 AF XY: 0.00265 AC XY: 1928 AN XY: 727180

African (AFR) AF: 0.106 AC: 3536 AN: 33474

American (AMR) AF: 0.00572 AC: 256 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53320

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111962

Other (OTH) AF: 0.00651 AC: 393 AN: 60394

GnomAD4 genome AF: 0.0282 AC: 4294 AN: 152290 Hom.: 208 Cov.: 32 AF XY: 0.0266 AC XY: 1983 AN XY: 74458

African (AFR) AF: 0.0978 AC: 4065 AN: 41556

American (AMR) AF: 0.0103 AC: 157 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68012

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0160 Hom.: 62

Bravo AF: 0.0321

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RFXANK-related disorder Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.20
PromoterAI		-0.017	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73922830; hg19: chr19-19310047;