19-19199238-A-G

Position:

• chr19-19199238-A-G

Variant summary

Our verdict is Benign. Variant got -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 donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.03724
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.203

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=-0.9).
• BP6: Variant 19-19199238-A-G is Benign according to our data. Variant chr19-19199238-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 328647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-19199238-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFXANK	NM_003721.4	c.712+4A>G		splice_donor_region_variant, intron_variant		ENST00000303088.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFXANK	ENST00000303088.9	c.712+4A>G		splice_donor_region_variant, intron_variant		1	NM_003721.4	P1

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

GnomAD3 exomes AF: 0.00773 AC: 1940 AN: 251104 Hom.: 91 AF XY: 0.00568 AC XY: 771 AN XY: 135838

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 SAS exome AF: 0.000490

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

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00651

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

Gnomad4 AFR AF: 0.0978

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0132 Hom.: 53

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

RFXANK-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs73922830; hg19: chr19-19310047;