6-33076149-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002121.6(HLA-DPB1):c.100+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,579,764 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (34 hom.)
• Consequence: HLA-DPB1 NM_002121.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002491
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.148

Genes affected

HLA-DPB1 (HGNC:4940): (major histocompatibility complex, class II, DP beta 1) HLA-DPB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta chain (DPB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

HLA-DPA1 (HGNC:4938): (major histocompatibility complex, class II, DP alpha 1) HLA-DPA1 belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta (DPB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. 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. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-33076149-C-T is Benign according to our data. Variant chr6-33076149-C-T is described in ClinVar as [Benign]. Clinvar id is 725738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00356 (542/152306) while in subpopulation EAS AF= 0.0255 (132/5178). AF 95% confidence interval is 0.022. There are 3 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DPB1	NM_002121.6	c.100+8C>T		splice_region_variant, intron_variant		ENST00000418931.7
HLA-DPA1	NM_001242525.2	c.-23-2556G>A		intron_variant
HLA-DPA1	NM_001242524.2	c.-99-2480G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DPB1	ENST00000418931.7	c.100+8C>T		splice_region_variant, intron_variant			NM_002121.6	P1

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00312 AC: 707 AN: 226376 Hom.: 12 AF XY: 0.00323 AC XY: 398 AN XY: 123244

Gnomad AFR exome AF: 0.00674

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0240

Gnomad SAS exome AF: 0.00604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000496

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00104 AC: 1482 AN: 1427458 Hom.: 34 Cov.: 25 AF XY: 0.00122 AC XY: 867 AN XY: 710948

Gnomad4 AFR exome AF: 0.00669

Gnomad4 AMR exome AF: 0.000899

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0116

Gnomad4 SAS exome AF: 0.00606

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000240

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00377 AC XY: 281 AN XY: 74484

Gnomad4 AFR AF: 0.00835

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00129 Hom.: 2

Bravo AF: 0.00390

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.1
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs143352256; hg19: chr6-33043926;