rs17875380

Variant names:

• chr6-29723805-C-A
• rs17875380
• NM_001098479.2:c.212C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001098479.2(HLA-F):​c.212C>A​(p.Pro71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,606,318 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0095 (15 hom., cov: 34)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: HLA-F NM_001098479.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.740

Genes affected

HLA-F (HGNC:4963): (major histocompatibility complex, class I, F) This gene belongs to the HLA class I heavy chain paralogues. It encodes a non-classical heavy chain that forms a heterodimer with a beta-2 microglobulin light chain, with the heavy chain anchored in the membrane. Unlike most other HLA heavy chains, this molecule is localized in the endoplasmic reticulum and Golgi apparatus, with a small amount present at the cell surface in some cell types. It contains a divergent peptide-binding groove, and is thought to bind a restricted subset of peptides for immune presentation. This gene exhibits few polymorphisms. Multiple transcript variants encoding different isoforms have been found for this gene. These variants lack a coding exon found in transcripts from other HLA paralogues due to an altered splice acceptor site, resulting in a shorter cytoplasmic domain. [provided by RefSeq, Jul 2008]

ENSG00000225864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016821384).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00952 (1451/152344) while in subpopulation NFE AF = 0.0162 (1100/68032). AF 95% confidence interval is 0.0154. There are 15 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-F	NM_001098479.2	c.212C>A	p.Pro71Gln	missense_variant	Exon 2 of 7	ENST00000259951.12	NP_001091949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-F	ENST00000259951.12	c.212C>A	p.Pro71Gln	missense_variant	Exon 2 of 7	6	NM_001098479.2	ENSP00000259951.6

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1451 AN: 152226 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.0102 AC: 2346 AN: 229750 AF XY: 0.0106

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.0000594

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.00787

GnomAD4 exome AF: 0.0121 AC: 17550 AN: 1453974 Hom.: 141 Cov.: 41 AF XY: 0.0118 AC XY: 8530 AN XY: 722774

Gnomad4 AFR exome AF: 0.00174 AC: 58 AN: 33262

Gnomad4 AMR exome AF: 0.00212 AC: 93 AN: 43776

Gnomad4 ASJ exome AF: 0.000886 AC: 23 AN: 25956

Gnomad4 EAS exome AF: 0.0000509 AC: 2 AN: 39270

Gnomad4 SAS exome AF: 0.00859 AC: 733 AN: 85354

Gnomad4 FIN exome AF: 0.0112 AC: 579 AN: 51756

Gnomad4 NFE exome AF: 0.0140 AC: 15575 AN: 1108788

Gnomad4 Remaining exome AF: 0.00735 AC: 442 AN: 60110

GnomAD4 genome AF: 0.00952 AC: 1451 AN: 152344 Hom.: 15 Cov.: 34 AF XY: 0.00909 AC XY: 677 AN XY: 74496

Gnomad4 AFR AF: 0.00303 AC: 0.00303016 AN: 0.00303016

Gnomad4 AMR AF: 0.00209 AC: 0.00209041 AN: 0.00209041

Gnomad4 ASJ AF: 0.00115 AC: 0.00115274 AN: 0.00115274

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0108 AC: 0.010775 AN: 0.010775

Gnomad4 FIN AF: 0.0113 AC: 0.0112973 AN: 0.0112973

Gnomad4 NFE AF: 0.0162 AC: 0.0161689 AN: 0.0161689

Gnomad4 OTH AF: 0.00425 AC: 0.00425331 AN: 0.00425331

Alfa AF: 0.0128 Hom.: 40

Bravo AF: 0.00800

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00365 AC: 11

ESP6500EA AF: 0.0128 AC: 69

ExAC AF: 0.0108 AC: 1299

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.3
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.22	.;T;T;T
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.0060	B;B;B;B
Vest4		0.038
MPC		0.73
ClinPred		0.085	T
GERP RS		1.6
Varity_R		0.17
gMVP		0.38
Mutation Taster		=96/4	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

Publications

LitVar

Other links and lift over

dbSNP: rs17875380; hg19: chr6-29691582;