6-32580255-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_002124.4(HLA-DRB1):c.779A>C(p.Gln260Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. Q260Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 16)
  • Exomes 𝑓: 0.00037 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), 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. The beta chain is approximately 26-28 kDa. It is encoded by 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 DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25858185).
• BP6: Variant 6-32580255-T-G is Benign according to our data. Variant chr6-32580255-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2656458.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.779A>C	p.Gln260Pro	missense_variant	5/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.779A>C	p.Gln260Pro	missense_variant	5/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 718 AN: 112620 Hom.: 6 Cov.: 16 FAILED QC

Gnomad AFR AF: 0.00973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00620

Gnomad ASJ AF: 0.00824

Gnomad EAS AF: 0.00730

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00435

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00895

GnomAD3 exomes AF: 0.0000199 AC: 4 AN: 200728 Hom.: 0 AF XY: 0.0000273 AC XY: 3 AN XY: 109972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000459

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.000205

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000372 AC: 351 AN: 944708 Hom.: 7 Cov.: 15 AF XY: 0.000456 AC XY: 220 AN XY: 482630

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000518

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.000339

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.000924

Gnomad4 NFE exome AF: 0.0000923

Gnomad4 OTH exome AF: 0.000394

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00639 AC: 720 AN: 112738 Hom.: 6 Cov.: 16 AF XY: 0.00652 AC XY: 357 AN XY: 54750

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.00620

Gnomad4 ASJ AF: 0.00824

Gnomad4 EAS AF: 0.00734

Gnomad4 SAS AF: 0.0171

Gnomad4 FIN AF: 0.00435

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00881

Alfa AF: 0.00901 Hom.: 9

ESP6500AA AF: 0.00167 AC: 7

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.000213 AC: 25

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

HLA-DRB1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.94	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Uncertain	0.022	D
Sift4G	Benign	0.14	T
Polyphen		0.36	B
Vest4		0.53
MVP		0.49
MPC		0.87
ClinPred		0.069	T
GERP RS		4.0
Varity_R		0.32
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17887154; hg19: chr6-32548032;