rs771206465

Variant names:

• chr6-32519641-C-G
• rs771206465
• NM_002125.4:c.381G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-32519641-C-G
• chr6-32519641-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002125.4(HLA-DRB5):​c.381G>C​(p.Lys127Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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. K127K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 3)
  • Exomes 𝑓: 0.000033 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11157611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.381G>C	p.Lys127Asn	missense_variant	Exon 3 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.381G>C	p.Lys127Asn	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.381G>C	p.Lys127Asn	missense_variant	Exon 3 of 6	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.371-80G>C		intron_variant	Intron 2 of 5			ENSP00000519744.1

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD2 exomes AF: 0.0000899 AC: 8 AN: 88952 AF XY: 0.000164

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 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: 0.0000330 AC: 20 AN: 606698 Hom.: 8 Cov.: 7 AF XY: 0.0000452 AC XY: 14 AN XY: 309508

African (AFR) AF: 0.00 AC: 0 AN: 12578

American (AMR) AF: 0.00 AC: 0 AN: 19724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11250

East Asian (EAS) AF: 0.00 AC: 0 AN: 24270

South Asian (SAS) AF: 0.000465 AC: 20 AN: 43022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 435808

Other (OTH) AF: 0.00 AC: 0 AN: 28148

GnomAD4 genome Cov.: 3

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000136 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.20	T
Polyphen		0.23	B
Vest4		0.24
MutPred		0.31		Loss of methylation at K127 (P = 0.0098);
MVP		0.21
MPC		1.7
ClinPred		0.062	T
GERP RS		1.5
Varity_R		0.44
gMVP		0.21
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771206465; hg19: chr6-32487418;