ENST00000422832.1:c.-12+541T>A

Variant names:

• chr6-32968461-A-T
• rs206787
• ENST00000422832.1:c.-12+541T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000422832.1(HLA-DMA):​c.-12+541T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 152,246 control chromosomes in the GnomAD database, including 31,604 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (31579 hom., cov: 34)
  • Exomes 𝑓: 0.65 (25 hom.)
• Consequence: HLA-DMA ENST00000422832.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53
• Publications: 5 publications found

Genes affected

HLA-DMA (HGNC:4934): (major histocompatibility complex, class II, DM alpha) HLA-DMA belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DMA) and a beta chain (DMB), both anchored in the membrane. It is located in intracellular vesicles. DM plays a central role in the peptide loading of MHC class II molecules by helping to release the CLIP molecule from the peptide binding site. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. [provided by RefSeq, Jul 2008]

LOC124901302 (HGNC:):

BRD2 (HGNC:1103): (bromodomain containing 2) This gene encodes a transcriptional regulator that belongs to the BET (bromodomains and extra terminal domain) family of proteins. This protein associates with transcription complexes and with acetylated chromatin during mitosis, and it selectively binds to the acetylated lysine-12 residue of histone H4 via its two bromodomains. The gene maps to the major histocompatability complex (MHC) class II region on chromosome 6p21.3, but sequence comparison suggests that the protein is not involved in the immune response. This gene has been implicated in juvenile myoclonic epilepsy, a common form of epilepsy that becomes apparent in adolescence. Multiple alternatively spliced variants have been described for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000422832.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOC124901302	NR_190903.1		n.61T>A		non_coding_transcript_exon	Exon 1 of 2
	LOC124901302	NR_190904.1		n.61T>A		non_coding_transcript_exon	Exon 1 of 3
	BRD2	NM_005104.4	MANE Select	c.-1900A>T		upstream_gene	N/A	NP_005095.1	P25440-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DMA	ENST00000422832.1	TSL:6	c.-12+541T>A		intron	N/A	ENSP00000403122.1	F6S093
	BRD2	ENST00000374825.9	TSL:1 MANE Select	c.-1900A>T		upstream_gene	N/A	ENSP00000363958.4	P25440-1
	HLA-DMA	ENST00000464392.1	TSL:6	n.-17T>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96821 AN: 152018 Hom.: 31539 Cov.: 34

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.645 AC: 71 AN: 110 Hom.: 25 Cov.: 0 AF XY: 0.643 AC XY: 54 AN XY: 84

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.500 AC: 2 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.750 AC: 3 AN: 4

European-Non Finnish (NFE) AF: 0.670 AC: 63 AN: 94

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.637 AC: 96909 AN: 152136 Hom.: 31579 Cov.: 34 AF XY: 0.633 AC XY: 47101 AN XY: 74380

African (AFR) AF: 0.778 AC: 32313 AN: 41538

American (AMR) AF: 0.545 AC: 8335 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2190 AN: 3466

East Asian (EAS) AF: 0.504 AC: 2592 AN: 5146

South Asian (SAS) AF: 0.524 AC: 2528 AN: 4826

European-Finnish (FIN) AF: 0.630 AC: 6682 AN: 10606

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40283 AN: 67940

Other (OTH) AF: 0.629 AC: 1328 AN: 2110

Alfa AF: 0.533 Hom.: 1666

Bravo AF: 0.637

Asia WGS AF: 0.552 AC: 1923 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.43
DANN	Benign	0.79
PhyloP100		-2.5
PromoterAI		0.18	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs206787; hg19: chr6-32936238; COSMIC: COSV66374650;