NM_002116.8:c.383G>C

Variant names:

• chr6-29943307-G-C
• rs199474493
• NM_002116.8:c.383G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002116.8(HLA-A):​c.383G>C​(p.Gly128Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 8)
  • Exomes 𝑓: 0.0000027 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 0 publications found

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. More than 6000 HLA-A alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

POLR1HASP (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. 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-A	NM_002116.8	MANE Select	c.383G>C	p.Gly128Ala	missense	Exon 3 of 8	NP_002107.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.383G>C	p.Gly128Ala	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.383G>C	p.Gly128Ala	missense	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.383G>C	p.Gly128Ala	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 61754 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000270 AC: 2 AN: 741966 Hom.: 1 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 376240

African (AFR) AF: 0.00 AC: 0 AN: 20700

American (AMR) AF: 0.00 AC: 0 AN: 22184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12926

East Asian (EAS) AF: 0.00 AC: 0 AN: 14502

South Asian (SAS) AF: 0.00 AC: 0 AN: 55532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2638

European-Non Finnish (NFE) AF: 0.00000364 AC: 2 AN: 549824

Other (OTH) AF: 0.00 AC: 0 AN: 31656

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 61754 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 29856

African (AFR) AF: 0.00 AC: 0 AN: 18738

American (AMR) AF: 0.00 AC: 0 AN: 4598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1180

East Asian (EAS) AF: 0.00 AC: 0 AN: 1198

South Asian (SAS) AF: 0.00 AC: 0 AN: 1402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28222

Other (OTH) AF: 0.00 AC: 0 AN: 762

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.00098	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.92	T
PhyloP100		0.049
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.094
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.091
MutPred		0.81		Loss of methylation at R132 (P = 0.13)
MVP		0.53
MPC		0.48
ClinPred		0.95	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs199474493; hg19: chr6-29911084;