rs707956

Positions:

• chr6-32522079-C-A
• chr6-32522079-C-G
• chr6-32522079-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002125.4(HLA-DRB5):​c.196G>T​(p.Asp66Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. D66N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (24851 hom., cov: 13)
  • Exomes 𝑓: 0.82 (394091 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.46

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, 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 and its gene contains 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. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7771125E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.196G>T	p.Asp66Tyr	missense_variant	2/6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.196G>T	p.Asp66Tyr	missense_variant	2/6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4	c.196G>T	p.Asp66Tyr	missense_variant	2/6		NM_002125.4	ENSP00000364114	P1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 63610 AN: 86656 Hom.: 24834 Cov.: 13

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.836

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.764

GnomAD3 exomes AF: 0.0861 AC: 6707 AN: 77858 Hom.: 2762 AF XY: 0.0800 AC XY: 3409 AN XY: 42600

Gnomad AFR exome AF: 0.0677

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0563

Gnomad SAS exome AF: 0.0451

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.102

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.817 AC: 900695 AN: 1102176 Hom.: 394091 Cov.: 31 AF XY: 0.816 AC XY: 449526 AN XY: 551010

Gnomad4 AFR exome AF: 0.717

Gnomad4 AMR exome AF: 0.815

Gnomad4 ASJ exome AF: 0.876

Gnomad4 EAS exome AF: 0.624

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.819

Gnomad4 NFE exome AF: 0.832

Gnomad4 OTH exome AF: 0.798

GnomAD4 genome AF: 0.734 AC: 63644 AN: 86706 Hom.: 24851 Cov.: 13 AF XY: 0.724 AC XY: 29896 AN XY: 41268

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.852

Gnomad4 EAS AF: 0.495

Gnomad4 SAS AF: 0.571

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.787

Gnomad4 OTH AF: 0.752

Alfa AF: 0.0859 Hom.: 15

ExAC AF: 0.402 AC: 30407

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0010
DANN	Benign	0.17
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-3.4
Eigen_PC	Benign	-3.3
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.6	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.051
MPC		0.018
ClinPred		0.0068	T
GERP RS		-9.6
Varity_R		0.23
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs707956; hg19: chr6-32489856; COSMIC: COSV66612446;