chr6-32519620-C-G

Variant names:

• chr6-32519620-C-G
• rs202054400
• NM_002125.4:c.402G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002125.4(HLA-DRB5):​c.402G>C​(p.Arg134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R134R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 7)
  • Exomes 𝑓: 0.0000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.166

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14377668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.402G>C	p.Arg134Ser	missense_variant	Exon 3 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.402G>C	p.Arg134Ser	missense_variant	Exon 3 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4	c.402G>C	p.Arg134Ser	missense_variant	Exon 3 of 6	6	NM_002125.4	ENSP00000364114.3

Frequencies

GnomAD3 genomes Cov.: 7

GnomAD3 exomes AF: 0.0000167 AC: 2 AN: 119482 Hom.: 1 AF XY: 0.0000306 AC XY: 2 AN XY: 65382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000133 AC: 1 AN: 750406 Hom.: 0 Cov.: 11 AF XY: 0.00000261 AC XY: 1 AN XY: 383488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 7

ExAC AF: 0.0000184 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.57	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.041	D
Polyphen		0.0	B
Vest4		0.18
MutPred		0.61		Loss of sheet (P = 0.0357);
MVP		0.25
MPC		1.6
ClinPred		0.23	T
GERP RS		3.8
Varity_R		0.64
gMVP		0.30

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: rs202054400; hg19: chr6-32487397;