19-19192406-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_003721.4(RFXANK):c.-298C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 537,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

RFXANK
NM_003721.4 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.51

Publications

0 publications found

Variant links:

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 links:

BORCS8 (HGNC:37247): (BLOC-1 related complex subunit 8) Involved in heart development. Part of BORC complex. [provided by Alliance of Genome Resources, Apr 2022]

BORCS8 links:

BORCS8-MEF2B (HGNC:39979): (BORCS8-MEF2B readthrough) This gene represents numerous read-through transcripts that span GeneID:729991 and 100271849. Many read-through transcripts are predicted to be nonsense-mediated decay (NMD) candidates, and are thought to be non-coding. Some transcripts are predicted to be capable of translation reinitiation at a downstream AUG, resulting in expression of at least one isoform of myocyte enhancer factor 2B (MEF2B) from this read-through locus. At least one additional MEF2B variant and isoform can be expressed from a downstream promoter, and is annotated on GeneID:100271849. [provided by RefSeq, Oct 2010]

BORCS8-MEF2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000283 (43/152134) while in subpopulation NFE AF = 0.0005 (34/68020). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RFXANK	NM_003721.4	MANE Select	c.-298C>T	5_prime_UTR	Exon 1 of 10	NP_003712.1	O14593-1
RFXANK	NM_001370235.1		c.-298C>T	5_prime_UTR	Exon 1 of 10	NP_001357164.1
RFXANK	NM_001278727.2		c.-298C>T	5_prime_UTR	Exon 1 of 9	NP_001265656.1	O14593-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.-298C>T	5_prime_UTR	Exon 1 of 10	ENSP00000305071.2	O14593-1
RFXANK	ENST00000456252.7	TSL:1	c.-298C>T	5_prime_UTR	Exon 1 of 9	ENSP00000409138.2	O14593-3
BORCS8	ENST00000477565.3	TSL:1	c.-289G>A	5_prime_UTR	Exon 1 of 4	ENSP00000424833.1	Q96FH0-2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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:

0.000500

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000340

AC:

131

AN:

385088

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

AN XY:

202194

show subpopulations

African (AFR)

AF:

0.000374

AC:

AN:

10696

American (AMR)

AF:

0.00

AC:

AN:

15484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11902

East Asian (EAS)

AF:

0.00

AC:

AN:

26040

South Asian (SAS)

AF:

0.00

AC:

AN:

39480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1720

European-Non Finnish (NFE)

AF:

0.000532

AC:

123

AN:

231286

Other (OTH)

AF:

0.000177

AC:

AN:

22594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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

AF:

0.000283

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.000295

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

MHC class II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.2

(source)

DANN

Benign

0.80

PhyloP100

-1.5

PromoterAI

-0.0060

Neutral

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over