rs707957

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-32584282-G-A
• chr6-32584282-G-C
• chr6-32584282-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002124.4(HLA-DRB1):​c.197C>T​(p.Ser66Phe) 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. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S66Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.090 (48 hom., cov: 17)
  • Exomes 𝑓: 0.083 (1382 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015552342).
• BP6: Variant 6-32584282-G-A is Benign according to our data. Variant chr6-32584282-G-A is described in ClinVar as Benign. ClinVar VariationId is 1296897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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>T	p.Ser66Phe	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>T	p.Ser66Phe	missense	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.275C>T	p.Ser92Phe	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.197C>T	p.Ser66Phe	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 10188 AN: 112944 Hom.: 48 Cov.: 17

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0957

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0721

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0795 AC: 12280 AN: 154416 AF XY: 0.0826

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.0700

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0734

Gnomad OTH exome AF: 0.0829

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0828 AC: 96890 AN: 1170020 Hom.: 1382 Cov.: 35 AF XY: 0.0843 AC XY: 49505 AN XY: 587120

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

African (AFR) AF: 0.0921 AC: 2623 AN: 28484

American (AMR) AF: 0.0564 AC: 2234 AN: 39616

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1610 AN: 22992

East Asian (EAS) AF: 0.123 AC: 4420 AN: 35892

South Asian (SAS) AF: 0.128 AC: 9519 AN: 74318

European-Finnish (FIN) AF: 0.0400 AC: 1859 AN: 46510

Middle Eastern (MID) AF: 0.117 AC: 583 AN: 4980

European-Non Finnish (NFE) AF: 0.0804 AC: 69762 AN: 867818

Other (OTH) AF: 0.0866 AC: 4280 AN: 49410

⚠️ 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: 0.0902 AC: 10198 AN: 113058 Hom.: 48 Cov.: 17 AF XY: 0.0896 AC XY: 4889 AN XY: 54588

African (AFR) AF: 0.115 AC: 3456 AN: 29966

American (AMR) AF: 0.0696 AC: 786 AN: 11298

Ashkenazi Jewish (ASJ) AF: 0.0721 AC: 206 AN: 2858

East Asian (EAS) AF: 0.170 AC: 664 AN: 3914

South Asian (SAS) AF: 0.134 AC: 431 AN: 3212

European-Finnish (FIN) AF: 0.0468 AC: 341 AN: 7284

Middle Eastern (MID) AF: 0.0647 AC: 15 AN: 232

European-Non Finnish (NFE) AF: 0.0784 AC: 4085 AN: 52130

Other (OTH) AF: 0.100 AC: 147 AN: 1464

Alfa AF: 0.132 Hom.: 633

ExAC AF: 0.120 AC: 14466

ClinVar

ClinVar submissions as Germline

Significance: 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	0.098
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0010
DANN	Benign	0.20
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-3.9
Eigen_PC	Benign	-3.9
FATHMM_MKL	Benign	0.00069	N
LIST_S2	Benign	0.028	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.80	T
PhyloP100		-6.4
PROVEAN	Benign	2.8	N
REVEL	Benign	0.055
Sift	Benign	0.50	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.78
ClinPred		0.013	T
GERP RS		-7.0
Varity_R		0.21
gMVP		0.23
Mutation Taster		=75/25	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; COSMIC: COSV63512983;