rs193240312

chr13-36819767-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000538.4(RFXAP):c.410T>C(p.Met137Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,562,270 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M137I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.016 (258 hom.)
• Consequence: RFXAP NM_000538.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.122

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022221506).
• BP6: Variant 13-36819767-T-C is Benign according to our data. Variant chr13-36819767-T-C is described in ClinVar as [Benign]. Clinvar id is 311787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-36819767-T-C is described in Lovd as [Benign]. Variant chr13-36819767-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1747/152102) while in subpopulation NFE AF= 0.017 (1152/67964). AF 95% confidence interval is 0.0161. There are 21 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFXAP	NM_000538.4	c.410T>C	p.Met137Thr	missense_variant	1/3	ENST00000255476.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFXAP	ENST00000255476.3	c.410T>C	p.Met137Thr	missense_variant	1/3	1	NM_000538.4	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1747 AN: 151984 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0138 AC: 2352 AN: 170576 Hom.: 32 AF XY: 0.0146 AC XY: 1329 AN XY: 90948

Gnomad AFR exome AF: 0.00331

Gnomad AMR exome AF: 0.00681

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0000790

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.00298

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0159 AC: 22489 AN: 1410168 Hom.: 258 Cov.: 32 AF XY: 0.0162 AC XY: 11256 AN XY: 696538

Gnomad4 AFR exome AF: 0.00277

Gnomad4 AMR exome AF: 0.00759

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.000136

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.00422

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0115 AC: 1747 AN: 152102 Hom.: 21 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74354

Gnomad4 AFR AF: 0.00292

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0170 Hom.: 50

Bravo AF: 0.0117

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.0176 AC: 150

ExAC AF: 0.0104 AC: 1233

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	13
Dann	Benign	0.52
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.027
Sift	Benign	0.39	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.062
MPC		1.1
ClinPred		0.00052	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.049

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: rs193240312; hg19: chr13-37393904; COSMIC: COSV55226536;