6-32444611-T-G

Variant names:

• chr6-32444611-T-G
• rs4935356
• NM_019111.5:c.*12-41T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019111.5(HLA-DRA):​c.*12-41T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 151,926 control chromosomes in the GnomAD database, including 18,793 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 0.49 (18793 hom., cov: 31)
  • Exomes 𝑓: 0.50 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRA NM_019111.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0970

Genes affected

HLA-DRA (HGNC:4947): (major histocompatibility complex, class II, DR alpha) HLA-DRA is one of the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha and a beta chain, both anchored in the membrane. This molecule is expressed on the surface of various antigen presenting cells such as B lymphocytes, dendritic cells, and monocytes/macrophages, and plays a central role in the immune system and response by presenting peptides derived from extracellular proteins, in particular, pathogen-derived peptides to T cells. The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and the cytoplasmic tail. DRA does not have polymorphisms in the peptide binding part and acts as the sole alpha chain for DRB1, DRB3, DRB4 and DRB5. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.*12-41T>G		intron_variant	Intron 4 of 4	ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.*12-41T>G		intron_variant	Intron 4 of 4	6	NM_019111.5	ENSP00000378786.2
HLA-DRA	ENST00000374982.5	c.*12-41T>G		intron_variant	Intron 4 of 4	6		ENSP00000364121.5

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74196 AN: 151808 Hom.: 18783 Cov.: 31

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.525

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.489 AC: 74242 AN: 151926 Hom.: 18793 Cov.: 31 AF XY: 0.486 AC XY: 36129 AN XY: 74278

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.529

Alfa AF: 0.435 Hom.: 3127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4935356; hg19: chr6-32412388;