19-19201687-C-T

Variant names:

• chr19-19201687-C-T
• rs1802498
• NM_003721.4:c.751C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001370238.1(RFXANK):​c.826C>T​(p.Gln276*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RFXANK NM_001370238.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• Publications: 13 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0373 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370238.1. 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.751C>T	p.Gln251*	stop_gained	Exon 10 of 10	NP_003712.1
	NR2C2AP	NM_176880.6	MANE Select	c.*238G>A		3_prime_UTR	Exon 5 of 5	NP_795361.1
	RFXANK	NM_001370238.1		c.826C>T	p.Gln276*	stop_gained	Exon 10 of 10	NP_001357167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.751C>T	p.Gln251*	stop_gained	Exon 10 of 10	ENSP00000305071.2
	RFXANK	ENST00000407360.7	TSL:1	c.751C>T	p.Gln251*	stop_gained	Exon 9 of 9	ENSP00000384572.3
	RFXANK	ENST00000456252.7	TSL:1	c.685C>T	p.Gln229*	stop_gained	Exon 9 of 9	ENSP00000409138.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251010 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.5
Vest4		0.80
GERP RS		4.8
Mutation Taster		=23/177	disease causing

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

dbSNP: rs1802498; hg19: chr19-19312496;