NM_019111.5:c.354A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 64 publications found

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]

ENSG00000299747 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019111.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRA	NM_019111.5	MANE Select	c.354A>G	p.Thr118Thr	synonymous	Exon 3 of 5	NP_061984.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRA	ENST00000395388.7	TSL:6 MANE Select	c.354A>G	p.Thr118Thr	synonymous	Exon 3 of 5	ENSP00000378786.2
	HLA-DRA	ENST00000374982.5	TSL:6	c.329-50A>G		intron	N/A	ENSP00000364121.5
	ENSG00000299747	ENST00000766007.1		n.163-4950T>C		intron	N/A

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

GnomAD2 exomes AF: 0.912 AC: 224848 AN: 246534 AF XY: 0.914

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 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

African (AFR) AF: 0.953 AC: 31906 AN: 33466

American (AMR) AF: 0.950 AC: 42464 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 25493 AN: 26128

East Asian (EAS) AF: 0.999 AC: 39644 AN: 39700

South Asian (SAS) AF: 0.981 AC: 84643 AN: 86246

European-Finnish (FIN) AF: 0.862 AC: 45108 AN: 52306

Middle Eastern (MID) AF: 0.953 AC: 5496 AN: 5766

European-Non Finnish (NFE) AF: 0.857 AC: 952053 AN: 1110290

Other (OTH) AF: 0.887 AC: 53501 AN: 60300

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

African (AFR) AF: 0.948 AC: 39370 AN: 41542

American (AMR) AF: 0.927 AC: 14181 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3395 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5161 AN: 5180

South Asian (SAS) AF: 0.980 AC: 4724 AN: 4818

European-Finnish (FIN) AF: 0.871 AC: 9207 AN: 10572

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58504 AN: 68000

Other (OTH) AF: 0.932 AC: 1971 AN: 2114

Alfa AF: 0.884 Hom.: 211092

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.32
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3135391; hg19: chr6-32410987;