chr19-19201648-G-A

Variant names:

• chr19-19201648-G-A
• rs2060720733
• NM_176880.6:c.*277C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003721.4(RFXANK):​c.713-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFXANK NM_003721.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 8.05
• Publications: 0 publications found

Genes affected

NR2C2AP (HGNC:30763): (nuclear receptor 2C2 associated protein) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.2, offset of 8, new splice context is: gccccatctcaatgcaacAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-19201648-G-A is Pathogenic according to our data. Variant chr19-19201648-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2C2AP	NM_176880.6	c.*277C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000331552.12	NP_795361.1
RFXANK	NM_003721.4	c.713-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 9	ENST00000303088.9	NP_003712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2C2AP	ENST00000331552.12	c.*277C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_176880.6	ENSP00000332823.6
RFXANK	ENST00000303088.9	c.713-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 9	1	NM_003721.4	ENSP00000305071.2
NR2C2AP	ENST00000420605.7	c.415-85C>T		intron_variant	Intron 5 of 5	2		ENSP00000402756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Pathogenic:2 Uncertain:1

Sep 05, 2019

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 07, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		8.1
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 9
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs2060720733; hg19: chr19-19312457;