6-32968461-A-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124901302	NR_190903.1	n.61T>A		non_coding_transcript_exon_variant	Exon 1 of 2
LOC124901302	NR_190904.1	n.61T>A		non_coding_transcript_exon_variant	Exon 1 of 3
BRD2	NM_005104.4	c.-1900A>T		upstream_gene_variant		ENST00000374825.9	NP_005095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DMA	ENST00000422832.1	c.-12+541T>A		intron_variant	Intron 1 of 2	6		ENSP00000403122.1
BRD2	ENST00000374825.9	c.-1900A>T		upstream_gene_variant		1	NM_005104.4	ENSP00000363958.4
HLA-DMA	ENST00000464392.1	n.-17T>A		upstream_gene_variant		6

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

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.778

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.629

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.43
DANN	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

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