rs76451666

Positions:

• chr4-56650683-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145460.2(HOPX):​c.328G>A​(p.Glu110Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,550,766 control chromosomes in the GnomAD database, including 3,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.047 (254 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3097 hom.)
• Consequence: HOPX NM_001145460.2 missense, splice_region
• Scores: Splicing: ADA: 0.7131
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

Genes affected

HOPX (HGNC:24961): (HOP homeobox) The protein encoded by this gene is a homeodomain protein that lacks certain conserved residues required for DNA binding. It was reported that choriocarcinoma cell lines and tissues failed to express this gene, which suggested the possible involvement of this gene in malignant conversion of placental trophoblasts. Studies in mice suggest that this protein may interact with serum response factor (SRF) and modulate SRF-dependent cardiac-specific gene expression and cardiac development. Multiple alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015913248).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOPX	NM_032495.6	c.199-1886G>A		intron_variant		ENST00000420433.6	NP_115884.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOPX	ENST00000420433.6	c.199-1886G>A		intron_variant		5	NM_032495.6	ENSP00000396275.1

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7213 AN: 152130 Hom.: 255 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0484

GnomAD3 exomes AF: 0.0470 AC: 7400 AN: 157336 Hom.: 231 AF XY: 0.0465 AC XY: 3864 AN XY: 83156

Gnomad AFR exome AF: 0.00989

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0763

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0714

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0628 AC: 87823 AN: 1398518 Hom.: 3097 Cov.: 30 AF XY: 0.0619 AC XY: 42713 AN XY: 689826

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0394

Gnomad4 ASJ exome AF: 0.0775

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0714

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0474 AC: 7209 AN: 152248 Hom.: 254 Cov.: 32 AF XY: 0.0454 AC XY: 3380 AN XY: 74438

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0507

Gnomad4 ASJ AF: 0.0775

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.0431

Gnomad4 NFE AF: 0.0719

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0650 Hom.: 533

Bravo AF: 0.0470

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0641 AC: 247

ExAC AF: 0.0377 AC: 963

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.93
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.062
Sift	Benign	0.23	T;T
Sift4G	Benign	0.29	T;T
Vest4		0.19
MPC		0.34
ClinPred		0.016	T
GERP RS		3.0
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Benign	0.27
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: rs76451666; hg19: chr4-57516849;