6-32522079-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. D66D) 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
• 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 -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 rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.196G>A	p.Asp66Asn	missense_variant	Exon 2 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.196G>A	p.Asp66Asn	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>A	p.Asp66Asn	missense_variant	Exon 2 of 6	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.196G>A	p.Asp66Asn	missense_variant	Exon 2 of 6			ENSP00000519744.1

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

GnomAD2 exomes AF: 0.263 AC: 20454 AN: 77858 AF XY: 0.278

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 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

African (AFR) AF: 0.116 AC: 3029 AN: 26086

American (AMR) AF: 0.135 AC: 5560 AN: 41150

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2510 AN: 22530

East Asian (EAS) AF: 0.266 AC: 9496 AN: 35748

South Asian (SAS) AF: 0.153 AC: 11401 AN: 74380

European-Finnish (FIN) AF: 0.0583 AC: 2775 AN: 47622

Middle Eastern (MID) AF: 0.117 AC: 570 AN: 4874

European-Non Finnish (NFE) AF: 0.0383 AC: 35807 AN: 935418

Other (OTH) AF: 0.0686 AC: 3531 AN: 51444

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

African (AFR) AF: 0.124 AC: 2732 AN: 21992

American (AMR) AF: 0.121 AC: 1013 AN: 8368

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 262 AN: 2094

East Asian (EAS) AF: 0.304 AC: 960 AN: 3158

South Asian (SAS) AF: 0.236 AC: 597 AN: 2530

European-Finnish (FIN) AF: 0.0852 AC: 538 AN: 6312

Middle Eastern (MID) AF: 0.129 AC: 18 AN: 140

European-Non Finnish (NFE) AF: 0.0460 AC: 2178 AN: 47384

Other (OTH) AF: 0.109 AC: 128 AN: 1170

Alfa AF: 0.00 Hom.: 15

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

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Other links and lift over

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