chr6-29943261-G-A

Variant names:

• chr6-29943261-G-A
• rs41554914
• NM_002116.8:c.344-7G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6_Moderate

The NM_002116.8(HLA-A):​c.344-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 5)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 splice_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.853
• 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: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-29943261-G-A is Benign according to our data. Variant chr6-29943261-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2656329.Status of the report is criteria_provided_single_submitter, 1 stars.

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.344-7G>A		splice_region intron	N/A	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.344-7G>A		splice_region intron	N/A	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.344-7G>A		splice_region intron	N/A	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.344-7G>A		splice_region intron	N/A	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0000961 AC: 5 AN: 52010 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000278

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000790 AC: 166 AN: 210204 AF XY: 0.00105

Gnomad AFR exome AF: 0.0000754

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000750

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000118 AC: 83 AN: 702118 Hom.: 0 Cov.: 9 AF XY: 0.000170 AC XY: 60 AN XY: 352904

⚠️ 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: 19544

American (AMR) AF: 0.00 AC: 0 AN: 16770

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 4 AN: 11584

East Asian (EAS) AF: 0.000384 AC: 5 AN: 13034

South Asian (SAS) AF: 0.00111 AC: 55 AN: 49730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29206

Middle Eastern (MID) AF: 0.000426 AC: 1 AN: 2350

European-Non Finnish (NFE) AF: 0.0000302 AC: 16 AN: 529700

Other (OTH) AF: 0.0000662 AC: 2 AN: 30200

⚠️ 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: 0.0000961 AC: 5 AN: 52032 Hom.: 0 Cov.: 5 AF XY: 0.0000794 AC XY: 2 AN XY: 25198

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

African (AFR) AF: 0.00 AC: 0 AN: 12894

American (AMR) AF: 0.000277 AC: 1 AN: 3604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 962

East Asian (EAS) AF: 0.00 AC: 0 AN: 972

South Asian (SAS) AF: 0.00 AC: 0 AN: 1160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5114

Middle Eastern (MID) AF: 0.0116 AC: 1 AN: 86

European-Non Finnish (NFE) AF: 0.000114 AC: 3 AN: 26224

Other (OTH) AF: 0.00 AC: 0 AN: 648

⚠️ 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: 0.000240 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.96
PhyloP100		0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 24
DS_AL_spliceai		0.51		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41554914; hg19: chr6-29911038;