Genetic Variant RFXAP:p.Pro26Leu (chr13-36819434-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000538.4(RFXAP):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000077 in 1,298,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

RFXAP
NM_000538.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.951

Publications

0 publications found

Variant links:

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

RFXAP links:

ENSG00000309469 (HGNC:):

ENSG00000309469 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13023537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXAP	NM_000538.4 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 3	ENST00000255476.3	NP_000529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXAP	ENST00000255476.3 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 3	1	NM_000538.4	ENSP00000255476.3
ENSG00000309469	ENST00000841309.1 link	n.122+143G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

70866

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.70e-7

AC:

AN:

1298638

Hom.:

Cov.:

AF XY:

0.00000157

AC XY:

AN XY:

637178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26576

American (AMR)

AF:

0.00

AC:

AN:

22094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20464

East Asian (EAS)

AF:

0.00

AC:

AN:

30424

South Asian (SAS)

AF:

0.00

AC:

AN:

63288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4926

European-Non Finnish (NFE)

AF:

9.66e-7

AC:

AN:

1034976

Other (OTH)

AF:

0.00

AC:

AN:

53534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

0.95

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.5

REVEL

Benign

0.080

Sift

Uncertain

0.0070

Sift4G

Benign

0.16

Polyphen

0.61

Vest4

0.21

MutPred

0.23

Gain of helix (P = 0.0078);

MVP

0.11

MPC

0.95

ClinPred

0.43

GERP RS

4.0

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.077

gMVP

0.20

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over