rs9269955

Positions:

• chr6-32584361-G-A
• chr6-32584361-G-C
• chr6-32584361-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002124.4(HLA-DRB1):​c.118C>T​(p.Pro40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 11)
  • Exomes 𝑓: 0.00023 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -10.4

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]

HLA-DRB1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009984314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.118C>T	p.Pro40Ser	missense_variant	2/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.118C>T	p.Pro40Ser	missense_variant	2/6	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.0000892 AC: 7 AN: 78482 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000435

Gnomad ASJ AF: 0.000497

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000288

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000465 AC: 3 AN: 64458 Hom.: 0 AF XY: 0.0000560 AC XY: 2 AN XY: 35728

Gnomad AFR exome AF: 0.000277

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000877

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000569

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000230 AC: 164 AN: 713888 Hom.: 2 Cov.: 11 AF XY: 0.000222 AC XY: 82 AN XY: 369898

Gnomad4 AFR exome AF: 0.000409

Gnomad4 AMR exome AF: 0.000441

Gnomad4 ASJ exome AF: 0.000415

Gnomad4 EAS exome AF: 0.000399

Gnomad4 SAS exome AF: 0.000224

Gnomad4 FIN exome AF: 0.000161

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.000380

GnomAD4 genome AF: 0.0000891 AC: 7 AN: 78572 Hom.: 0 Cov.: 11 AF XY: 0.0000793 AC XY: 3 AN XY: 37848

Gnomad4 AFR AF: 0.0000849

Gnomad4 AMR AF: 0.000434

Gnomad4 ASJ AF: 0.000497

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000288

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00475 AC: 368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0010
DANN	Benign	0.17
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.045	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.034
Sift	Benign	0.58	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.040
MPC		0.72
ClinPred		0.022	T
GERP RS		-7.0
Varity_R		0.092
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9269955; hg19: chr6-32552138;