rs707956

Variant names:

• chr6-32522079-C-A
• rs707956
• NM_002125.4:c.196G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D66N) has been classified as 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
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 6	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 6			ENSP00000519744.1

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

GnomAD2 exomes AF: 0.0861 AC: 6707 AN: 77858 AF XY: 0.0800

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 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

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

African (AFR) AF: 0.717 AC: 16605 AN: 23160

American (AMR) AF: 0.815 AC: 32017 AN: 39262

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 18505 AN: 21122

East Asian (EAS) AF: 0.624 AC: 18836 AN: 30168

South Asian (SAS) AF: 0.748 AC: 47563 AN: 63580

European-Finnish (FIN) AF: 0.819 AC: 34503 AN: 42140

Middle Eastern (MID) AF: 0.848 AC: 3780 AN: 4456

European-Non Finnish (NFE) AF: 0.832 AC: 692505 AN: 832684

Other (OTH) AF: 0.798 AC: 36381 AN: 45604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.644 AC: 13265 AN: 20586

American (AMR) AF: 0.759 AC: 6140 AN: 8092

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 1698 AN: 1992

East Asian (EAS) AF: 0.495 AC: 1338 AN: 2704

South Asian (SAS) AF: 0.571 AC: 1287 AN: 2254

European-Finnish (FIN) AF: 0.739 AC: 4278 AN: 5788

Middle Eastern (MID) AF: 0.820 AC: 105 AN: 128

European-Non Finnish (NFE) AF: 0.787 AC: 34250 AN: 43532

Other (OTH) AF: 0.752 AC: 823 AN: 1094

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
PhyloP100		-4.5
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs707956; hg19: chr6-32489856; COSMIC: COSV66612446;