6-32642006-C-T

Variant names:

• chr6-32642006-C-T
• rs1048124
• NM_002122.5:c.366C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_002122.5(HLA-DQA1):​c.366C>T​(p.Pro122Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 17)
  • Exomes 𝑓: 0.000083 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.38
• Publications: 0 publications found

Genes affected

HLA-DQA1 (HGNC:4942): (major histocompatibility complex, class II, DQ alpha 1) HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), 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 (APC: B Lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa. It is encoded by 5 exons; exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.025).
• BP6: Variant 6-32642006-C-T is Benign according to our data. Variant chr6-32642006-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2656471.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.366C>T	p.Pro122Pro	synonymous_variant	Exon 3 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.366C>T	p.Pro122Pro	synonymous_variant	Exon 3 of 4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.366C>T	p.Pro122Pro	synonymous_variant	Exon 3 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 20 AN: 116350 Hom.: 1 Cov.: 17

Gnomad AFR AF: 0.000377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246684 AF XY: 0.00

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: 0.0000829 AC: 119 AN: 1434700 Hom.: 5 Cov.: 36 AF XY: 0.0000756 AC XY: 54 AN XY: 714234

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

African (AFR) AF: 0.00115 AC: 37 AN: 32214

American (AMR) AF: 0.000184 AC: 8 AN: 43374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 34948

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49224

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5638

European-Non Finnish (NFE) AF: 0.0000573 AC: 63 AN: 1098814

Other (OTH) AF: 0.000102 AC: 6 AN: 58956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000172 AC: 20 AN: 116446 Hom.: 1 Cov.: 17 AF XY: 0.000177 AC XY: 10 AN XY: 56440

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

African (AFR) AF: 0.000375 AC: 12 AN: 31972

American (AMR) AF: 0.00 AC: 0 AN: 9806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2706

East Asian (EAS) AF: 0.00 AC: 0 AN: 3364

South Asian (SAS) AF: 0.00 AC: 0 AN: 3828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000147 AC: 8 AN: 54282

Other (OTH) AF: 0.00 AC: 0 AN: 1548

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0165 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HLA-DQA1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0030
DANN	Benign	0.32
PhyloP100		-5.4
Mutation Taster		=100/0	polymorphism

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: rs1048124; hg19: chr6-32609783;