chr6-29945521-A-T

Variant names:

• chr6-29945521-A-T
• rs1061235
• NM_002116.8:c.*66A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):​c.*66A>T variant causes a 3 prime UTR 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 risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (3 hom., cov: 24)
  • Exomes 𝑓: 0.0054 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 3_prime_UTR
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.347
• Publications: 46 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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.*66A>T		3_prime_UTR	Exon 8 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.*66A>T		3_prime_UTR	Exon 8 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.*66A>T		3_prime_UTR	Exon 8 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.*148A>T		3_prime_UTR	Exon 8 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3195 AN: 142960 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00444

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0218

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0428

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0242

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00536 AC: 4410 AN: 822874 Hom.: 4 Cov.: 12 AF XY: 0.00579 AC XY: 2478 AN XY: 428224

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

African (AFR) AF: 0.00870 AC: 172 AN: 19762

American (AMR) AF: 0.00916 AC: 299 AN: 32628

Ashkenazi Jewish (ASJ) AF: 0.00777 AC: 141 AN: 18152

East Asian (EAS) AF: 0.0272 AC: 880 AN: 32370

South Asian (SAS) AF: 0.0145 AC: 907 AN: 62420

European-Finnish (FIN) AF: 0.00631 AC: 253 AN: 40108

Middle Eastern (MID) AF: 0.0107 AC: 46 AN: 4288

European-Non Finnish (NFE) AF: 0.00259 AC: 1489 AN: 574648

Other (OTH) AF: 0.00579 AC: 223 AN: 38498

⚠️ 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: AS_VQSR AF: 0.0224 AC: 3210 AN: 143072 Hom.: 3 Cov.: 24 AF XY: 0.0236 AC XY: 1639 AN XY: 69568

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

African (AFR) AF: 0.0285 AC: 1080 AN: 37904

American (AMR) AF: 0.0285 AC: 401 AN: 14086

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 72 AN: 3306

East Asian (EAS) AF: 0.0414 AC: 190 AN: 4588

South Asian (SAS) AF: 0.0550 AC: 232 AN: 4218

European-Finnish (FIN) AF: 0.0261 AC: 265 AN: 10134

Middle Eastern (MID) AF: 0.0426 AC: 12 AN: 282

European-Non Finnish (NFE) AF: 0.0138 AC: 907 AN: 65686

Other (OTH) AF: 0.0239 AC: 47 AN: 1968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0315 Hom.: 0

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Carbamazepine hypersensitivity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1061235; hg19: chr6-29913298; COSMIC: COSV65139711; COSMIC: COSV65139711;