6-32584314-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F55Y) has been classified as Likely 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

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 2499006.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00812 (1048/129136) while in subpopulation EAS AF= 0.0277 (109/3942). AF 95% confidence interval is 0.0234. There are 11 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.165C>A	p.Phe55Leu	missense_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.165C>A	p.Phe55Leu	missense_variant	2/6		NM_002124.4	P1

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

GnomAD3 exomes AF: 0.0000176 AC: 3 AN: 170260 Hom.: 0 AF XY: 0.0000107 AC XY: 1 AN XY: 93542

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.00986

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.00696

GnomAD4 genome AF: 0.00812 AC: 1048 AN: 129136 Hom.: 11 Cov.: 20 AF XY: 0.00817 AC XY: 510 AN XY: 62446

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00364

Gnomad4 ASJ AF: 0.00963

Gnomad4 EAS AF: 0.0277

Gnomad4 SAS AF: 0.00487

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.00443

Gnomad4 OTH AF: 0.00873

Alfa AF: 0.00823 Hom.: 229

ExAC AF: 0.0000518 AC: 6

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

HLA-DRB1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1059572; hg19: chr6-32552091; COSMIC: COSV63513837;