rs75289558

Variant names:

• chr6-32745222-C-G
• rs75289558
• NM_020056.5:c.146C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32745222-C-G
• chr6-32745222-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_020056.5(HLA-DQA2):​c.146C>G​(p.Thr49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA2 NM_020056.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.880
• Publications: 9 publications found

Genes affected

HLA-DQA2 (HGNC:4943): (major histocompatibility complex, class II, DQ alpha 2) This gene belongs to the HLA class II alpha chain family. The encoded protein forms a heterodimer with a class II beta chain. It is located in intracellular vesicles and plays a central role in the peptide loading of MHC class II molecules by helping to release the CLIP molecule from the peptide binding site. Class II molecules are expressed in antigen presenting cells (B lymphocytes, dendritic cells, macrophages) and are used to present antigenic peptides on the cell surface to be recognized by CD4 T-cells. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03749454).
• BP6: Variant 6-32745222-C-G is Benign according to our data. Variant chr6-32745222-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2681314.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020056.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA2	NM_020056.5	MANE Select	c.146C>G	p.Thr49Ser	missense	Exon 2 of 5	NP_064440.1	P01906

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA2	ENST00000374940.4	TSL:6 MANE Select	c.146C>G	p.Thr49Ser	missense	Exon 2 of 5	ENSP00000364076.3	P01906

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 799 AN: 136936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00252

Gnomad AMI AF: 0.00622

Gnomad AMR AF: 0.00758

Gnomad ASJ AF: 0.00822

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.00242

Gnomad FIN AF: 0.00858

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00368

GnomAD2 exomes AF: 0.0000999 AC: 25 AN: 250188 AF XY: 0.0000812

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000531 AC: 754 AN: 1419348 Hom.: 0 Cov.: 32 AF XY: 0.000651 AC XY: 458 AN XY: 703966

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

African (AFR) AF: 0.000213 AC: 7 AN: 32886

American (AMR) AF: 0.00152 AC: 60 AN: 39494

Ashkenazi Jewish (ASJ) AF: 0.000568 AC: 14 AN: 24658

East Asian (EAS) AF: 0.00232 AC: 87 AN: 37518

South Asian (SAS) AF: 0.000205 AC: 17 AN: 83006

European-Finnish (FIN) AF: 0.00344 AC: 170 AN: 49384

Middle Eastern (MID) AF: 0.000536 AC: 3 AN: 5592

European-Non Finnish (NFE) AF: 0.000332 AC: 361 AN: 1088358

Other (OTH) AF: 0.000599 AC: 35 AN: 58452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00585 AC: 802 AN: 137018 Hom.: 0 Cov.: 32 AF XY: 0.00602 AC XY: 403 AN XY: 66902

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

African (AFR) AF: 0.00252 AC: 99 AN: 39332

American (AMR) AF: 0.00772 AC: 103 AN: 13336

Ashkenazi Jewish (ASJ) AF: 0.00822 AC: 25 AN: 3040

East Asian (EAS) AF: 0.0219 AC: 91 AN: 4146

South Asian (SAS) AF: 0.00264 AC: 12 AN: 4546

European-Finnish (FIN) AF: 0.00858 AC: 79 AN: 9210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00631 AC: 381 AN: 60416

Other (OTH) AF: 0.00364 AC: 7 AN: 1922

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0305 Hom.: 0

ExAC AF: 0.000972 AC: 118

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EBV-positive nodal T- and NK-cell lymphoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.88
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.17	T
Polyphen		0.016	B
Vest4		0.35
MutPred		0.38		Loss of phosphorylation at T49 (P = 0.0467)
MVP		0.21
MPC		0.41
ClinPred		0.023	T
GERP RS		3.2
Varity_R		0.090
gMVP		0.17
Mutation Taster		=93/7	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: rs75289558; hg19: chr6-32712999; COSMIC: COSV66565327; COSMIC: COSV66565327;