chr6-30491353-A-C

Position:

• chr6-30491353-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005516.6(HLA-E):​c.827A>C​(p.Gln276Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,614,186 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: HLA-E NM_005516.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.181

Genes affected

HLA-E (HGNC:4962): (major histocompatibility complex, class I, E) HLA-E 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. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00931409).
• BP6: Variant 6-30491353-A-C is Benign according to our data. Variant chr6-30491353-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 708684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-E	NM_005516.6	c.827A>C	p.Gln276Pro	missense_variant	4/8	ENST00000376630.5	NP_005507.3
HLA-E	XM_017010807.2	c.950A>C	p.Gln317Pro	missense_variant	3/7		XP_016866296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-E	ENST00000376630.5	c.827A>C	p.Gln276Pro	missense_variant	4/8	6	NM_005516.6	ENSP00000365817.4

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00167 AC: 419 AN: 251096 Hom.: 1 AF XY: 0.00159 AC XY: 216 AN XY: 135776

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00284 AC: 4158 AN: 1461868 Hom.: 8 Cov.: 32 AF XY: 0.00272 AC XY: 1979 AN XY: 727236

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74482

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00159

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000662 AC: 2

ESP6500EA AF: 0.00277 AC: 15

ExAC AF: 0.00170 AC: 207

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00409

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.0085
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.082
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Vest4		0.26
MVP		0.41
MPC		1.8
ClinPred		0.058	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.45
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs141487266; hg19: chr6-30459130;