rs1555302467

Variant names:

• chr13-36819415-C-T
• rs1555302467
• NM_000538.4:c.58C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000538.4(RFXAP):​c.58C>T​(p.His20Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H20R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RFXAP NM_000538.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.18
• Publications: 0 publications found

Genes affected

RFXAP (HGNC:9988): (regulatory factor X associated 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 ankyrin-containing 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. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group D. Transcript variants utilizing different polyA signals have been found for this gene. [provided by RefSeq, Jul 2008]

RFXAP Gene-Disease associations (from GenCC):

• MHC class II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000309469 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067560285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXAP	NM_000538.4	c.58C>T	p.His20Tyr	missense_variant	Exon 1 of 3	ENST00000255476.3	NP_000529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXAP	ENST00000255476.3	c.58C>T	p.His20Tyr	missense_variant	Exon 1 of 3	1	NM_000538.4	ENSP00000255476.3
ENSG00000309469	ENST00000841309.1	n.122+162G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000255 AC: 3 AN: 1178684 Hom.: 1 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 568494

African (AFR) AF: 0.00 AC: 0 AN: 23560

American (AMR) AF: 0.00 AC: 0 AN: 9578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15838

East Asian (EAS) AF: 0.00 AC: 0 AN: 27626

South Asian (SAS) AF: 0.0000841 AC: 3 AN: 35656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3876

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 979318

Other (OTH) AF: 0.00 AC: 0 AN: 48220

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Uncertain:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 471261). This variant has not been reported in the literature in individuals affected with RFXAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 20 of the RFXAP protein (p.His20Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.2
DANN	Benign	0.94
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.23		Gain of catalytic residue at H20 (P = 6e-04);
MVP		0.11
MPC		1.1
ClinPred		0.084	T
GERP RS		2.4
PromoterAI		-0.067	Neutral
Varity_R		0.046
gMVP		0.056
Mutation Taster		=98/2	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: rs1555302467; hg19: chr13-37393552;