rs201676379

chr19-19198704-A-Cchr19-19198704-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003721.4(RFXANK):c.612A>C(p.Lys204Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,236 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. K204K) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RFXANK NM_003721.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.456

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4007485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFXANK	NM_003721.4	c.612A>C	p.Lys204Asn	missense_variant	8/10	ENST00000303088.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFXANK	ENST00000303088.9	c.612A>C	p.Lys204Asn	missense_variant	8/10	1	NM_003721.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T;.;T;.;T;.
Eigen	Benign	0.058
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.70	N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N;N;.;.;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.068	T;T;.;.;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.64
MutPred		0.47		Loss of methylation at K204 (P = 0.0058);.;Loss of methylation at K204 (P = 0.0058);.;.;.;
MVP		0.75
MPC		0.95
ClinPred		0.84	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201676379; hg19: chr19-19309513;