NM_002116.8:c.448C>T

Variant names:

• chr6-29943372-C-T
• rs1059506
• NM_002116.8:c.448C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002116.8(HLA-A):​c.448C>T​(p.Leu150Leu) 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 no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.081 (580 hom., cov: 6)
  • Exomes 𝑓: 0.10 (27559 hom.)
• Consequence: HLA-A NM_002116.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• Publications: 15 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.985 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

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.448C>T	p.Leu150Leu	synonymous	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.448C>T	p.Leu150Leu	synonymous	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.448C>T	p.Leu150Leu	synonymous	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.448C>T	p.Leu150Leu	synonymous	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 4159 AN: 51654 Hom.: 568 Cov.: 6

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0870

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0784

Gnomad NFE AF: 0.0609

Gnomad OTH AF: 0.0786

GnomAD2 exomes AF: 0.128 AC: 31157 AN: 244132 AF XY: 0.128

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.0850

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.102 AC: 97908 AN: 961512 Hom.: 27559 Cov.: 19 AF XY: 0.103 AC XY: 49475 AN XY: 480676

African (AFR) AF: 0.131 AC: 2785 AN: 21312

American (AMR) AF: 0.150 AC: 3688 AN: 24544

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 2038 AN: 15400

East Asian (EAS) AF: 0.291 AC: 5051 AN: 17382

South Asian (SAS) AF: 0.137 AC: 8698 AN: 63644

European-Finnish (FIN) AF: 0.0519 AC: 1674 AN: 32270

Middle Eastern (MID) AF: 0.0983 AC: 293 AN: 2982

European-Non Finnish (NFE) AF: 0.0934 AC: 69638 AN: 745344

Other (OTH) AF: 0.105 AC: 4043 AN: 38634

GnomAD4 genome AF: 0.0810 AC: 4188 AN: 51718 Hom.: 580 Cov.: 6 AF XY: 0.0777 AC XY: 1943 AN XY: 25006

African (AFR) AF: 0.120 AC: 1713 AN: 14280

American (AMR) AF: 0.108 AC: 418 AN: 3866

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 86 AN: 988

East Asian (EAS) AF: 0.102 AC: 101 AN: 990

South Asian (SAS) AF: 0.116 AC: 130 AN: 1120

European-Finnish (FIN) AF: 0.0345 AC: 165 AN: 4776

Middle Eastern (MID) AF: 0.0833 AC: 8 AN: 96

European-Non Finnish (NFE) AF: 0.0609 AC: 1501 AN: 24648

Other (OTH) AF: 0.0769 AC: 50 AN: 650

Alfa AF: 0.118 Hom.: 537

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1059506; hg19: chr6-29911149; COSMIC: COSV65138946; COSMIC: COSV65138946;