chr19-19192376-G-A

Variant names:

• chr19-19192376-G-A
• rs62135502
• NM_003721.4:c.-328G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003721.4(RFXANK):​c.-328G>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 0.132 in 579,840 control chromosomes in the GnomAD database, including 6,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1243 hom., cov: 32)
  • Exomes 𝑓: 0.14 (4965 hom.)
• Consequence: RFXANK NM_003721.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.335
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-19192376-G-A is Benign according to our data. Variant chr19-19192376-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4	c.-328G>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000303088.9	NP_003712.1
BORCS8	NM_001145784.2	c.-259C>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.-328G>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_003721.4	ENSP00000305071.2
BORCS8	ENST00000462790.8	c.-259C>T		upstream_gene_variant		1	NM_001145784.2	ENSP00000425864.1
BORCS8-MEF2B	ENST00000514819.7	c.-385C>T		upstream_gene_variant		5		ENSP00000454967.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16849 AN: 152094 Hom.: 1245 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.140 AC: 59680 AN: 427628 Hom.: 4965 Cov.: 3 AF XY: 0.141 AC XY: 31614 AN XY: 224616

African (AFR) AF: 0.0268 AC: 314 AN: 11704

American (AMR) AF: 0.0711 AC: 1256 AN: 17666

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 1627 AN: 13076

East Asian (EAS) AF: 0.000306 AC: 9 AN: 29408

South Asian (SAS) AF: 0.126 AC: 5501 AN: 43756

European-Finnish (FIN) AF: 0.182 AC: 5226 AN: 28700

Middle Eastern (MID) AF: 0.125 AC: 236 AN: 1884

European-Non Finnish (NFE) AF: 0.164 AC: 42195 AN: 256588

Other (OTH) AF: 0.133 AC: 3316 AN: 24846

GnomAD4 genome AF: 0.111 AC: 16844 AN: 152212 Hom.: 1243 Cov.: 32 AF XY: 0.111 AC XY: 8254 AN XY: 74410

African (AFR) AF: 0.0280 AC: 1165 AN: 41554

American (AMR) AF: 0.0849 AC: 1298 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.110 AC: 532 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1914 AN: 10592

Middle Eastern (MID) AF: 0.144 AC: 42 AN: 292

European-Non Finnish (NFE) AF: 0.164 AC: 11164 AN: 67996

Other (OTH) AF: 0.106 AC: 223 AN: 2104

Alfa AF: 0.114 Hom.: 575

Bravo AF: 0.0966

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.68
PhyloP100		0.34
PromoterAI		-0.0088	Neutral
Mutation Taster		=299/1	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: rs62135502; hg19: chr19-19303185;