Genetic Variant NM_002116.8:c.448C>T (chr6-29943372-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.985

Variant links:

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]

HLA-A links:

LOC124901298 (HGNC:):

LOC124901298 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.448C>T	p.Leu150Leu	synonymous_variant	Exon 3 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1409G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.448C>T	p.Leu150Leu	synonymous_variant	Exon 3 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

4159

AN:

51654

Hom.:

568

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.128

AC:

31157

AN:

244132

Hom.:

2337

AF XY:

0.128

AC XY:

17081

AN XY:

133336

show subpopulations

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 SAS exome

AF:

0.164

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.:

AF XY:

0.103

AC XY:

49475

AN XY:

480676

show subpopulations

Gnomad4 AFR exome

AF:

0.131

Gnomad4 AMR exome

AF:

0.150

Gnomad4 ASJ exome

AF:

0.132

Gnomad4 EAS exome

AF:

0.291

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.0519

Gnomad4 NFE exome

AF:

0.0934

Gnomad4 OTH exome

AF:

0.105

GnomAD4 genome

AF:

0.0810

AC:

4188

AN:

51718

Hom.:

580

Cov.:

AF XY:

0.0777

AC XY:

1943

AN XY:

25006

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.0870

Gnomad4 EAS

AF:

0.102

Gnomad4 SAS

AF:

0.116

Gnomad4 FIN

AF:

0.0345

Gnomad4 NFE

AF:

0.0609

Gnomad4 OTH

AF:

0.0769

Alfa

AF:

0.118

Hom.:

537

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over