NM_002124.4:c.779A>C

Variant names:

• chr6-32580255-T-G
• rs17887154
• NM_002124.4:c.779A>C

Variant summary

Our verdict is Likely benign. The variant received -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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
• Publications: 13 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=0.25858185).
• 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 VariationId is 2656458.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.779A>C	p.Gln260Pro	missense	Exon 5 of 6	NP_002115.2	P01911

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.779A>C	p.Gln260Pro	missense	Exon 5 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.857A>C	p.Gln286Pro	missense	Exon 5 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859898.1		c.689A>C	p.Gln230Pro	missense	Exon 5 of 6	ENSP00000529957.1

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 718 AN: 112620 Hom.: 6 Cov.: 16

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

GnomAD2 exomes AF: 0.0000199 AC: 4 AN: 200728 AF XY: 0.0000273

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 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

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

African (AFR) AF: 0.000242 AC: 6 AN: 24828

American (AMR) AF: 0.000518 AC: 17 AN: 32836

Ashkenazi Jewish (ASJ) AF: 0.000424 AC: 8 AN: 18876

East Asian (EAS) AF: 0.000339 AC: 9 AN: 26514

South Asian (SAS) AF: 0.00252 AC: 171 AN: 67966

European-Finnish (FIN) AF: 0.000924 AC: 43 AN: 46522

Middle Eastern (MID) AF: 0.00454 AC: 18 AN: 3966

European-Non Finnish (NFE) AF: 0.0000923 AC: 63 AN: 682542

Other (OTH) AF: 0.000394 AC: 16 AN: 40658

⚠️ 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 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

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

African (AFR) AF: 0.00970 AC: 303 AN: 31238

American (AMR) AF: 0.00620 AC: 60 AN: 9680

Ashkenazi Jewish (ASJ) AF: 0.00824 AC: 21 AN: 2548

East Asian (EAS) AF: 0.00734 AC: 24 AN: 3270

South Asian (SAS) AF: 0.0171 AC: 54 AN: 3160

European-Finnish (FIN) AF: 0.00435 AC: 34 AN: 7810

Middle Eastern (MID) AF: 0.00980 AC: 2 AN: 204

European-Non Finnish (NFE) AF: 0.00397 AC: 209 AN: 52692

Other (OTH) AF: 0.00881 AC: 13 AN: 1476

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0113 Hom.: 10

ESP6500AA AF: 0.00167 AC: 7

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.000213 AC: 25

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.2
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs17887154; hg19: chr6-32548032;