chr19-19201675-C-T

Variant names:

• chr19-19201675-C-T
• NM_003721.4:c.739C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003721.4(RFXANK):​c.739C>T​(p.Leu247Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L247L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFXANK NM_003721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 0 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]

NR2C2AP (HGNC:30763): (nuclear receptor 2C2 associated protein) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

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.739C>T	p.Leu247Phe	missense	Exon 10 of 10	NP_003712.1	O14593-1
	NR2C2AP	NM_176880.6	MANE Select	c.*250G>A		3_prime_UTR	Exon 5 of 5	NP_795361.1	Q86WQ0-1
	RFXANK	NM_001370238.1		c.814C>T	p.Leu272Phe	missense	Exon 10 of 10	NP_001357167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.739C>T	p.Leu247Phe	missense	Exon 10 of 10	ENSP00000305071.2	O14593-1
	RFXANK	ENST00000407360.7	TSL:1	c.739C>T	p.Leu247Phe	missense	Exon 9 of 9	ENSP00000384572.3	O14593-1
	RFXANK	ENST00000456252.7	TSL:1	c.673C>T	p.Leu225Phe	missense	Exon 9 of 9	ENSP00000409138.2	O14593-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.062	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.81		Gain of methylation at K248 (P = 0.0274)
MVP		0.89
MPC		0.94
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.32
gMVP		0.30
Mutation Taster		=35/65	disease causing

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

Other links and lift over

hg19: chr19-19312484;