19-19199176-C-G

Variant names:

• chr19-19199176-C-G
• rs8862
• NM_003721.4:c.654C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_003721.4(RFXANK):​c.654C>G​(p.Thr218Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,776 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. T218T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RFXANK NM_003721.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.44
• Publications: 2 publications found

Genes affected

RFXANK (HGNC:9987): (regulatory factor X associated ankyrin containing 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 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. This protein contains ankyrin repeats involved in protein-protein interactions. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group B. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2013]

RFXANK Gene-Disease associations (from GenCC):

• MHC class II deficiency

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07882124).
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003721.4. 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
	RFXANK	NM_003721.4	MANE Select	c.654C>G	p.Thr218Thr	synonymous	Exon 9 of 10	NP_003712.1	O14593-1
	RFXANK	NM_001370238.1		c.654C>G	p.Thr218Thr	synonymous	Exon 8 of 10	NP_001357167.1
	RFXANK	NM_001370237.1		c.651C>G	p.Thr217Thr	synonymous	Exon 8 of 10	NP_001357166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.654C>G	p.Thr218Thr	synonymous	Exon 9 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.654C>G	p.Thr218Thr	synonymous	Exon 8 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.588C>G	p.Thr196Thr	synonymous	Exon 8 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.50
DANN	Benign	0.83
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.90	T
PhyloP100		-4.4
PROVEAN	Benign	0.50	N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
MutPred		0.21		Loss of glycosylation at P176 (P = 0.0065)
MVP		0.22
ClinPred		0.069	T
GERP RS		-10
PromoterAI		0.19	Neutral
Mutation Taster		=100/0	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: rs8862; hg19: chr19-19309985;