NM_003721.4:c.8_11delTTAC

Variant names:

• chr19-19193952-GCTTA-G
• NM_003721.4:c.8_11delTTAC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003721.4(RFXANK):​c.8_11delTTAC​(p.Leu3ProfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RFXANK NM_003721.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.97
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-19193952-GCTTA-G is Pathogenic according to our data. Variant chr19-19193952-GCTTA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3362569.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	NM_003721.4	MANE Select	c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 3 of 10	NP_003712.1	O14593-1
	RFXANK	NM_001370238.1		c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 2 of 10	NP_001357167.1
	RFXANK	NM_001370237.1		c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 2 of 10	NP_001357166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 3 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 2 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.8_11delTTAC	p.Leu3ProfsTer47	frameshift	Exon 3 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	MHC class II deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chr19-19304761;