19-19201702-C-T

Variant names:

• chr19-19201702-C-T
• rs759707164
• NM_003721.4:c.766C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003721.4(RFXANK):​c.766C>T​(p.Pro256Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: RFXANK NM_003721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• 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]

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22974744).

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.766C>T	p.Pro256Ser	missense	Exon 10 of 10	NP_003712.1	O14593-1
	NR2C2AP	NM_176880.6	MANE Select	c.*223G>A		3_prime_UTR	Exon 5 of 5	NP_795361.1	Q86WQ0-1
	RFXANK	NM_001370238.1		c.841C>T	p.Pro281Ser	missense	Exon 10 of 10	NP_001357167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.766C>T	p.Pro256Ser	missense	Exon 10 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.766C>T	p.Pro256Ser	missense	Exon 9 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.700C>T	p.Pro234Ser	missense	Exon 9 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000758 AC: 19 AN: 250608 AF XY: 0.0000885

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: 0.000139

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727192

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53322

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

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1111986

Other (OTH) AF: 0.000116 AC: 7 AN: 60390

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000123 AC: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.10
MVP		0.89
MPC		0.26
ClinPred		0.16	T
GERP RS		5.0
Varity_R		0.10
gMVP		0.39
Mutation Taster		=79/21	polymorphism

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: rs759707164; hg19: chr19-19312511;