6-32443746-T-C

Position:

• chr6-32443746-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_019111.5(HLA-DRA):​c.611-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,564,834 control chromosomes in the GnomAD database, including 180,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.49 (18830 hom., cov: 31)
  • Exomes 𝑓: 0.47 (161344 hom.)
• Consequence: HLA-DRA NM_019111.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005100
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-32443746-T-C is Benign according to our data. Variant chr6-32443746-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.611-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.611-10T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_019111.5	ENSP00000378786	P1
HLA-DRA	ENST00000374982.5	c.536-10T>C		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000364121

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74280 AN: 151866 Hom.: 18820 Cov.: 31

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.564

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: 0.524

GnomAD3 exomes AF: 0.507 AC: 107239 AN: 211414 Hom.: 28901 AF XY: 0.512 AC XY: 58759 AN XY: 114692

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.675

Gnomad EAS exome AF: 0.684

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.464

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.470 AC: 663567 AN: 1412850 Hom.: 161344 Cov.: 33 AF XY: 0.476 AC XY: 332877 AN XY: 699732

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.554

Gnomad4 ASJ exome AF: 0.673

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.490

GnomAD4 genome AF: 0.489 AC: 74326 AN: 151984 Hom.: 18830 Cov.: 31 AF XY: 0.487 AC XY: 36157 AN XY: 74276

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.602

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.528

Alfa AF: 0.488 Hom.: 34593

Bravo AF: 0.511

Asia WGS AF: 0.597 AC: 2073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.012
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

Publications

LitVar

Other links and lift over

dbSNP: rs2239804; hg19: chr6-32411523; COSMIC: COSV66622831;