19-19192338-C-A

Variant names:

• chr19-19192338-C-A
• rs116660619
• NM_003721.4:c.-366C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003721.4(RFXANK):​c.-366C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00928 in 602,098 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (192 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (55 hom.)
• Consequence: RFXANK NM_003721.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.56
• Publications: 2 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]

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-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]

MEF2B (HGNC:6995): (myocyte enhancer factor 2B) The product of this gene is a member of the MADS/MEF2 family of DNA binding proteins. The protein is thought to regulate gene expression, including expression of the smooth muscle myosin heavy chain gene. This region undergoes considerable alternative splicing, with transcripts supporting two non-overlapping loci (GeneID 729991 and 100271849) as well as numerous read-through transcripts that span both loci (annotated as GeneID 4207). Several isoforms of this protein are expressed from either this locus or from some of the read-through transcripts annotated on GeneID 4207. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-19192338-C-A is Benign according to our data. Variant chr19-19192338-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 328634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.-366C>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000303088.9	NP_003712.1
BORCS8	NM_001145784.2	c.-221G>T		upstream_gene_variant		ENST00000462790.8	NP_001139256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9	c.-366C>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_003721.4	ENSP00000305071.2
BORCS8	ENST00000462790.8	c.-221G>T		upstream_gene_variant		1	NM_001145784.2	ENSP00000425864.1
BORCS8-MEF2B	ENST00000514819.7	c.-347G>T		upstream_gene_variant		5		ENSP00000454967.3

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4068 AN: 152102 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00338 AC: 1521 AN: 449878 Hom.: 55 Cov.: 5 AF XY: 0.00294 AC XY: 694 AN XY: 236002

African (AFR) AF: 0.0922 AC: 1103 AN: 11968

American (AMR) AF: 0.00693 AC: 125 AN: 18032

Ashkenazi Jewish (ASJ) AF: 0.00277 AC: 37 AN: 13372

East Asian (EAS) AF: 0.00 AC: 0 AN: 29408

South Asian (SAS) AF: 0.0000225 AC: 1 AN: 44392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29128

Middle Eastern (MID) AF: 0.00463 AC: 9 AN: 1942

European-Non Finnish (NFE) AF: 0.000178 AC: 49 AN: 275894

Other (OTH) AF: 0.00765 AC: 197 AN: 25742

GnomAD4 genome AF: 0.0267 AC: 4067 AN: 152220 Hom.: 192 Cov.: 32 AF XY: 0.0251 AC XY: 1868 AN XY: 74422

African (AFR) AF: 0.0932 AC: 3870 AN: 41512

American (AMR) AF: 0.00902 AC: 138 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68016

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0177 Hom.: 16

Bravo AF: 0.0303

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.81
PhyloP100		-1.6
PromoterAI		0.063	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs116660619; hg19: chr19-19303147;