NM_002124.4:c.165C>A

Variant names:

• chr6-32584314-G-T
• rs1059572
• NM_002124.4:c.165C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002124.4(HLA-DRB1):​c.165C>A​(p.Phe55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (11 hom., cov: 20)
  • Exomes 𝑓: 0.0056 (62 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.12
• Publications: 15 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027664542).
• BP6: Variant 6-32584314-G-T is Benign according to our data. Variant chr6-32584314-G-T is described in ClinVar as Benign. ClinVar VariationId is 2499006.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 11 Unknown gene

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.165C>A	p.Phe55Leu	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.165C>A	p.Phe55Leu	missense	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.243C>A	p.Phe81Leu	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.165C>A	p.Phe55Leu	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1044 AN: 129038 Hom.: 11 Cov.: 20

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00365

Gnomad ASJ AF: 0.00963

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.00487

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00443

Gnomad OTH AF: 0.00825

GnomAD2 exomes AF: 0.0000176 AC: 3 AN: 170260 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00560 AC: 6686 AN: 1193124 Hom.: 62 Cov.: 31 AF XY: 0.00541 AC XY: 3259 AN XY: 602244

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

African (AFR) AF: 0.0113 AC: 339 AN: 30000

American (AMR) AF: 0.00187 AC: 81 AN: 43388

Ashkenazi Jewish (ASJ) AF: 0.00986 AC: 239 AN: 24232

East Asian (EAS) AF: 0.0271 AC: 976 AN: 36074

South Asian (SAS) AF: 0.00273 AC: 220 AN: 80658

European-Finnish (FIN) AF: 0.00709 AC: 348 AN: 49106

Middle Eastern (MID) AF: 0.00185 AC: 10 AN: 5408

European-Non Finnish (NFE) AF: 0.00472 AC: 4118 AN: 873228

Other (OTH) AF: 0.00696 AC: 355 AN: 51030

⚠️ 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: 0.00812 AC: 1048 AN: 129136 Hom.: 11 Cov.: 20 AF XY: 0.00817 AC XY: 510 AN XY: 62446

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

African (AFR) AF: 0.0140 AC: 499 AN: 35542

American (AMR) AF: 0.00364 AC: 48 AN: 13186

Ashkenazi Jewish (ASJ) AF: 0.00963 AC: 30 AN: 3114

East Asian (EAS) AF: 0.0277 AC: 109 AN: 3942

South Asian (SAS) AF: 0.00487 AC: 19 AN: 3898

European-Finnish (FIN) AF: 0.00820 AC: 67 AN: 8170

Middle Eastern (MID) AF: 0.00746 AC: 2 AN: 268

European-Non Finnish (NFE) AF: 0.00443 AC: 259 AN: 58504

Other (OTH) AF: 0.00873 AC: 15 AN: 1718

⚠️ 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: 0.00823 Hom.: 229

ExAC AF: 0.0000518 AC: 6

ClinVar

ClinVar submissions

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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.3
DANN	Benign	0.33
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.1
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.36
Sift	Benign	0.31	T
Sift4G	Benign	0.45	T
Polyphen		0.0030	B
Vest4		0.029
MutPred		0.15		Loss of sheet (P = 0.1501)
MVP		0.085
MPC		0.84
ClinPred		0.053	T
GERP RS		-6.6
Varity_R		0.42
gMVP		0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1059572; hg19: chr6-32552091; COSMIC: COSV63513837;