6-32581830-T-C

Position:

• chr6-32581830-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_002124.4(HLA-DRB1):​c.379A>G​(p.Lys127Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 116,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.335

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Variant has high frequency in the EAS(0.00822909) population. However there is too low homozygotes in high coverage region: (expected more than 12, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.008461118).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0208 (2411/116040) while in subpopulation EAS AF= 0.0493 (173/3512). AF 95% confidence interval is 0.0433. There are 0 homozygotes in gnomad4. There are 1193 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.379A>G	p.Lys127Glu	missense_variant	3/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.379A>G	p.Lys127Glu	missense_variant	3/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 2409 AN: 115950 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.0365

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.0474

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0214

GnomAD3 exomes AF: 0.00319 AC: 451 AN: 141532 Hom.: 0 AF XY: 0.00284 AC XY: 220 AN XY: 77572

Gnomad AFR exome AF: 0.00548

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00313

Gnomad EAS exome AF: 0.00805

Gnomad SAS exome AF: 0.00192

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00464

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00384 AC: 3793 AN: 987968 Hom.: 0 Cov.: 27 AF XY: 0.00412 AC XY: 2063 AN XY: 500954

Gnomad4 AFR exome AF: 0.00609

Gnomad4 AMR exome AF: 0.00728

Gnomad4 ASJ exome AF: 0.00445

Gnomad4 EAS exome AF: 0.00911

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.00276

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.0208 AC: 2411 AN: 116040 Hom.: 0 Cov.: 22 AF XY: 0.0212 AC XY: 1193 AN XY: 56158

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0140

Gnomad4 EAS AF: 0.0493

Gnomad4 SAS AF: 0.0420

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0205

Alfa AF: 0.0163 Hom.: 49

ExAC AF: 0.0187 AC: 2268

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Benign	0.066	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.087
MPC		0.99
ClinPred		0.0012	T
GERP RS		1.0
Varity_R		0.31
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs17405219; hg19: chr6-32549607;