6-32584282-G-C

Variant names:

• chr6-32584282-G-C
• rs707957
• NM_002124.4:c.197C>G

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.197C>G​(p.Ser66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S66F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 17)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.35
• Publications: 28 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=0.06477192).

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.197C>G	p.Ser66Cys	missense	Exon 2 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.197C>G	p.Ser66Cys	missense	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.275C>G	p.Ser92Cys	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.197C>G	p.Ser66Cys	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 118112 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.01e-7 AC: 1 AN: 1249198 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 627764

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

African (AFR) AF: 0.00 AC: 0 AN: 30580

American (AMR) AF: 0.00 AC: 0 AN: 41862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 37504

South Asian (SAS) AF: 0.00 AC: 0 AN: 80624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 927140

Other (OTH) AF: 0.00 AC: 0 AN: 52876

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 118112 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 56860

African (AFR) AF: 0.00 AC: 0 AN: 31246

American (AMR) AF: 0.00 AC: 0 AN: 11698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3006

East Asian (EAS) AF: 0.00 AC: 0 AN: 4080

South Asian (SAS) AF: 0.00 AC: 0 AN: 3390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54746

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 633

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0010
DANN	Benign	0.62
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-3.1
Eigen_PC	Benign	-3.4
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.023	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.52	T
PhyloP100		-6.4
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.14
Sift	Benign	0.034	D
Sift4G	Benign	0.085	T
Polyphen		0.68	P
Vest4		0.14
MutPred		0.21		Loss of disorder (P = 0.0017)
MVP		0.061
MPC		0.74
ClinPred		0.46	T
GERP RS		-7.0
Varity_R		0.30
gMVP		0.32
Mutation Taster		=99/1	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: rs707957; hg19: chr6-32552059;