Genetic Variant RFXAP:p.Met137Arg (chr13-36819767-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000538.4(RFXAP):c.410T>G(p.Met137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. M137T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RFXAP
NM_000538.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.122

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06721291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXAP	NM_000538.4 link	c.410T>G	p.Met137Arg	missense_variant	Exon 1 of 3	ENST00000255476.3	NP_000529.1	O00287

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXAP	ENST00000255476.3 link	c.410T>G	p.Met137Arg	missense_variant	Exon 1 of 3	1	NM_000538.4	ENSP00000255476.3		O00287
ENSG00000309469	ENST00000841309.1 link	n.-69A>C		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32104

American (AMR)

AF:

0.00

AC:

AN:

37162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25322

East Asian (EAS)

AF:

0.00

AC:

AN:

36684

South Asian (SAS)

AF:

0.00

AC:

AN:

80328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1084694

Other (OTH)

AF:

0.00

AC:

AN:

58442

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

0.18

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.031

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.55

M_CAP

Benign

0.0079

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.12

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.2

REVEL

Benign

0.038

Sift

Benign

0.18

Sift4G

Uncertain

0.044

Polyphen

0.039

Vest4

0.23

MutPred

0.25

Gain of catalytic residue at S136 (P = 0);

MVP

0.030

MPC

1.5

ClinPred

0.10

GERP RS

-2.5

Varity_R

0.41

gMVP

0.10

Mutation Taster

=94/6

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