rs193240312

Variant names:

• chr13-36819767-T-C
• rs193240312
• NM_000538.4:c.410T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-36819767-T-C
• chr13-36819767-T-G

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:3
• Conservation: PhyloP100: 0.122
• Publications: 7 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000309469 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 311787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000538.4. 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
	RFXAP	NM_000538.4	MANE Select	c.410T>C	p.Met137Thr	missense	Exon 1 of 3	NP_000529.1	O00287

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXAP	ENST00000255476.3	TSL:1 MANE Select	c.410T>C	p.Met137Thr	missense	Exon 1 of 3	ENSP00000255476.3	O00287
	ENSG00000309469	ENST00000841309.1		n.-69A>G		upstream_gene	N/A

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

GnomAD2 exomes AF: 0.0138 AC: 2352 AN: 170576 AF XY: 0.0146

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 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

African (AFR) AF: 0.00277 AC: 89 AN: 32104

American (AMR) AF: 0.00759 AC: 282 AN: 37162

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1175 AN: 25322

East Asian (EAS) AF: 0.000136 AC: 5 AN: 36684

South Asian (SAS) AF: 0.0175 AC: 1404 AN: 80328

European-Finnish (FIN) AF: 0.00422 AC: 210 AN: 49736

Middle Eastern (MID) AF: 0.0282 AC: 161 AN: 5700

European-Non Finnish (NFE) AF: 0.0167 AC: 18133 AN: 1084690

Other (OTH) AF: 0.0176 AC: 1030 AN: 58442

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

African (AFR) AF: 0.00292 AC: 121 AN: 41502

American (AMR) AF: 0.00935 AC: 143 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4810

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1152 AN: 67964

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0159 Hom.: 83

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	MHC class II deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.12
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
Mutation Taster		=97/3	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: rs193240312; hg19: chr13-37393904; COSMIC: COSV55226536;