6-32522079-C-T

Position:

• chr6-32522079-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002125.4(HLA-DRB5):​c.196G>A​(p.Asp66Asn) 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. 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. D66Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.090 (970 hom., cov: 13)
  • Exomes 𝑓: 0.060 (7945 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013343692).
• BP6: Variant 6-32522079-C-T is Benign according to our data. Variant chr6-32522079-C-T is described in ClinVar as [Benign]. Clinvar id is 1294564.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.196G>A	p.Asp66Asn	missense_variant	2/6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.196G>A	p.Asp66Asn	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>A	p.Asp66Asn	missense_variant	2/6	6	NM_002125.4	ENSP00000364114.3

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 8424 AN: 93646 Hom.: 968 Cov.: 13

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0108

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.263 AC: 20454 AN: 77858 Hom.: 9170 AF XY: 0.278 AC XY: 11854 AN XY: 42600

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.415

Gnomad SAS exome AF: 0.465

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.243

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0603 AC: 74679 AN: 1239252 Hom.: 7945 Cov.: 31 AF XY: 0.0633 AC XY: 39244 AN XY: 620030

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0686

GnomAD4 genome AF: 0.0900 AC: 8432 AN: 93706 Hom.: 970 Cov.: 13 AF XY: 0.0955 AC XY: 4267 AN XY: 44676

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.0852

Gnomad4 NFE AF: 0.0460

Gnomad4 OTH AF: 0.109

ExAC AF: 0.190 AC: 14374

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

GeneDx

Feb 24, 2021

This variant is associated with the following publications: (PMID: 26503572) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0010
DANN	Benign	0.72
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-3.0
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.31	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.038
Sift	Benign	0.34	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.017
ClinPred		0.017	T
GERP RS		-9.6
Varity_R		0.25
gMVP		0.27

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: rs707956; hg19: chr6-32489856; COSMIC: COSV66612255;