6-32584172-C-G

Position:

• chr6-32584172-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002124.4(HLA-DRB1):​c.307G>C​(p.Ala103Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,183,246 control chromosomes in the GnomAD database, including 288 homozygotes. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A103E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (17 hom., cov: 14)
  • Exomes 𝑓: 0.0016 (271 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -4.91

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098617375).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0016 (1756/1096924) while in subpopulation AFR AF= 0.0291 (668/22936). AF 95% confidence interval is 0.0273. There are 271 homozygotes in gnomad4_exome. There are 864 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.307G>C	p.Ala103Pro	missense_variant	2/6	ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.307G>C	p.Ala103Pro	missense_variant	2/6		NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 327 AN: 86272 Hom.: 16 Cov.: 14

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.000319

Gnomad MID AF: 0.00704

Gnomad NFE AF: 0.000729

Gnomad OTH AF: 0.00264

GnomAD3 exomes AF: 0.000609 AC: 78 AN: 128120 Hom.: 9 AF XY: 0.000468 AC XY: 33 AN XY: 70438

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad SAS exome AF: 0.000461

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00160 AC: 1756 AN: 1096924 Hom.: 271 Cov.: 28 AF XY: 0.00156 AC XY: 864 AN XY: 552830

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000708

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0000529

Gnomad4 NFE exome AF: 0.000759

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00381 AC: 329 AN: 86322 Hom.: 17 Cov.: 14 AF XY: 0.00373 AC XY: 157 AN XY: 42068

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00302

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000359

Gnomad4 FIN AF: 0.000319

Gnomad4 NFE AF: 0.000729

Gnomad4 OTH AF: 0.00259

Alfa AF: 0.0848 Hom.: 17

ExAC AF: 0.00684 AC: 726

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Peritoneal Gliomatosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Treehouse Childhood Cancer Initiative, UC Santa Cruz

Aug 01, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.53
DANN	Benign	0.95
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.045	D
Sift4G	Benign	0.14	T
Polyphen		0.23	B
Vest4		0.37
MVP		0.061
MPC		1.6
ClinPred		0.020	T
GERP RS		0.63
Varity_R		0.52
gMVP		0.64

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: rs16822805; hg19: chr6-32551949; COSMIC: COSV63511934;