6-32443210-A-G

Variant names:

• chr6-32443210-A-G
• rs3135391
• NM_019111.5:c.354A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_019111.5(HLA-DRA):​c.354A>G​(p.Thr118Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.88 in 1,611,122 control chromosomes in the GnomAD database, including 626,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.90 (62394 hom., cov: 31)
  • Exomes 𝑓: 0.88 (563708 hom.)
• Consequence: HLA-DRA NM_019111.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33

Genes affected

HLA-DRA (HGNC:4947): (major histocompatibility complex, class II, DR alpha) HLA-DRA is one of the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha and a beta chain, both anchored in the membrane. This molecule is expressed on the surface of various antigen presenting cells such as B lymphocytes, dendritic cells, and monocytes/macrophages, and plays a central role in the immune system and response by presenting peptides derived from extracellular proteins, in particular, pathogen-derived peptides to T cells. The alpha chain is approximately 33-35 kDa and its gene contains 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. DRA does not have polymorphisms in the peptide binding part and acts as the sole alpha chain for DRB1, DRB3, DRB4 and DRB5. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 6-32443210-A-G is Benign according to our data. Variant chr6-32443210-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.354A>G	p.Thr118Thr	synonymous_variant	Exon 3 of 5	ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.354A>G	p.Thr118Thr	synonymous_variant	Exon 3 of 5	6	NM_019111.5	ENSP00000378786.2
HLA-DRA	ENST00000374982.5	c.329-50A>G		intron_variant	Intron 2 of 4	6		ENSP00000364121.5

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137509 AN: 152082 Hom.: 62340 Cov.: 31

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.931

GnomAD3 exomes AF: 0.912 AC: 224848 AN: 246534 Hom.: 103060 AF XY: 0.914 AC XY: 122805 AN XY: 134358

Gnomad AFR exome AF: 0.948

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.979

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.982

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.865

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.878 AC: 1280308 AN: 1458922 Hom.: 563708 Cov.: 51 AF XY: 0.881 AC XY: 639422 AN XY: 725880

Gnomad4 AFR exome AF: 0.953

Gnomad4 AMR exome AF: 0.950

Gnomad4 ASJ exome AF: 0.976

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.981

Gnomad4 FIN exome AF: 0.862

Gnomad4 NFE exome AF: 0.857

Gnomad4 OTH exome AF: 0.887

GnomAD4 genome AF: 0.904 AC: 137621 AN: 152200 Hom.: 62394 Cov.: 31 AF XY: 0.906 AC XY: 67373 AN XY: 74376

Gnomad4 AFR AF: 0.948

Gnomad4 AMR AF: 0.927

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.980

Gnomad4 FIN AF: 0.871

Gnomad4 NFE AF: 0.860

Gnomad4 OTH AF: 0.932

Alfa AF: 0.882 Hom.: 85682

Bravo AF: 0.911

Asia WGS AF: 0.980 AC: 3410 AN: 3478

EpiCase AF: 0.878

EpiControl AF: 0.887

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135391; hg19: chr6-32410987;