13-36819434-C-G

Position:

• chr13-36819434-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000538.4(RFXAP):​c.77C>G​(p.Pro26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,450,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RFXAP NM_000538.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.951

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066409707).
• BP6: Variant 13-36819434-C-G is Benign according to our data. Variant chr13-36819434-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311783.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFXAP	NM_000538.4	c.77C>G	p.Pro26Arg	missense_variant	1/3	ENST00000255476.3	NP_000529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFXAP	ENST00000255476.3	c.77C>G	p.Pro26Arg	missense_variant	1/3	1	NM_000538.4	ENSP00000255476	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000367 AC: 26 AN: 70866 Hom.: 0 AF XY: 0.000300 AC XY: 12 AN XY: 39940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000140 AC: 182 AN: 1298636 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 98 AN XY: 637176

Gnomad4 AFR exome AF: 0.0000376

Gnomad4 AMR exome AF: 0.000272

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000236

Gnomad4 NFE exome AF: 0.0000802

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74242

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.000566 Hom.: 1

Bravo AF: 0.000147

ExAC AF: 0.000127 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MHC class II deficiency Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.15
MutPred		0.24		Gain of helix (P = 0.005);
MVP		0.21
MPC		1.0
ClinPred		0.11	T
GERP RS		4.0
Varity_R		0.072
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs763162669; hg19: chr13-37393571;