rs9269955

Variant names:

• chr6-32584361-G-A
• rs9269955
• NM_002124.4:c.118C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.118C>T	p.Pro40Ser	missense_variant	Exon 2 of 6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.118C>T	p.Pro40Ser	missense_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.0000465 AC: 3 AN: 64458 AF XY: 0.0000560

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000409 AC: 8 AN: 19562

American (AMR) AF: 0.000441 AC: 13 AN: 29454

Ashkenazi Jewish (ASJ) AF: 0.000415 AC: 7 AN: 16884

East Asian (EAS) AF: 0.000399 AC: 11 AN: 27570

South Asian (SAS) AF: 0.000224 AC: 14 AN: 62464

European-Finnish (FIN) AF: 0.000161 AC: 6 AN: 37266

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3816

European-Non Finnish (NFE) AF: 0.000189 AC: 91 AN: 482640

Other (OTH) AF: 0.000380 AC: 13 AN: 34232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000849 AC: 2 AN: 23548

American (AMR) AF: 0.000434 AC: 3 AN: 6918

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 1 AN: 2012

East Asian (EAS) AF: 0.00 AC: 0 AN: 2488

South Asian (SAS) AF: 0.00 AC: 0 AN: 2224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.0000288 AC: 1 AN: 34758

Other (OTH) AF: 0.00 AC: 0 AN: 996

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000686732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 88

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
PhyloP100		-10
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs9269955; hg19: chr6-32552138;