chr6-29943287-A-C

Variant names:

• chr6-29943287-A-C
• rs1136695
• NM_002116.8:c.363A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_002116.8(HLA-A):​c.363A>C​(p.Ile121Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 0.0 (0 hom., cov: 5)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.67
• Publications: 30 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP7: Synonymous conserved (PhyloP=-4.67 with no splicing effect.

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.363A>C	p.Ile121Ile	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.363A>C	p.Ile121Ile	synonymous	Exon 3 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.363A>C	p.Ile121Ile	synonymous	Exon 3 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.363A>C	p.Ile121Ile	synonymous	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 48178 Hom.: 0 Cov.: 5

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: 0.00000295 AC: 2 AN: 679068 Hom.: 0 Cov.: 10 AF XY: 0.00000583 AC XY: 2 AN XY: 343282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18280

American (AMR) AF: 0.00 AC: 0 AN: 17060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11368

East Asian (EAS) AF: 0.00 AC: 0 AN: 12810

South Asian (SAS) AF: 0.00 AC: 0 AN: 50422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2342

European-Non Finnish (NFE) AF: 0.00000394 AC: 2 AN: 508164

Other (OTH) AF: 0.00 AC: 0 AN: 29110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 48178 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 23234

African (AFR) AF: 0.00 AC: 0 AN: 13932

American (AMR) AF: 0.00 AC: 0 AN: 3528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 926

East Asian (EAS) AF: 0.00 AC: 0 AN: 894

South Asian (SAS) AF: 0.00 AC: 0 AN: 1116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 84

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22572

Other (OTH) AF: 0.00 AC: 0 AN: 602

Alfa AF: 0.00 Hom.: 2709

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.8
DANN	Benign	0.59
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1136695; hg19: chr6-29911064;