13-36819408-C-G

Variant names:

• chr13-36819408-C-G
• rs2138212292
• NM_000538.4:c.51C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000538.4(RFXAP):​c.51C>G​(p.Gly17Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000086 in 1,162,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G17G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: RFXAP NM_000538.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.489
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000309469 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.

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.51C>G	p.Gly17Gly	synonymous	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.51C>G	p.Gly17Gly	synonymous	Exon 1 of 3	ENSP00000255476.3	O00287
	ENSG00000309469	ENST00000841309.1		n.122+169G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.60e-7 AC: 1 AN: 1162780 Hom.: 0 Cov.: 31 AF XY: 0.00000179 AC XY: 1 AN XY: 558720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23378

American (AMR) AF: 0.00 AC: 0 AN: 8980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15434

East Asian (EAS) AF: 0.00 AC: 0 AN: 27350

South Asian (SAS) AF: 0.00 AC: 0 AN: 32702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3450

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 970262

Other (OTH) AF: 0.00 AC: 0 AN: 47476

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.7
DANN	Benign	0.63
PhyloP100		-0.49
PromoterAI		-0.038	Neutral

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: rs2138212292; hg19: chr13-37393545;