dbSNP rs76451666: HOPX:c.199-1886G>A (chr4-56650683-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 15/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

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

Publications

8 publications found

Variant links:

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]

HOPX links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145460.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOPX	NM_032495.6	MANE Select	c.199-1886G>A		intron	N/A	NP_115884.4
HOPX	NM_001145460.2		c.328G>A	p.Glu110Lys	missense splice_region	Exon 4 of 5	NP_001138932.1	Q9BPY8-4
HOPX	NM_001145459.2		c.145-1886G>A		intron	N/A	NP_001138931.1	Q9BPY8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HOPX	ENST00000420433.6	TSL:5 MANE Select	c.199-1886G>A	intron	N/A	ENSP00000396275.1	Q9BPY8-3
HOPX	ENST00000317745.11	TSL:1	c.145-1886G>A	intron	N/A	ENSP00000315198.7	Q9BPY8-1
HOPX	ENST00000337881.12	TSL:1	c.145-1886G>A	intron	N/A	ENSP00000337330.7	Q9BPY8-1

Frequencies

GnomAD3 genomes

AF:

0.0474

AC:

7213

AN:

152130

Hom.:

255

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0470

AC:

7400

AN:

157336

AF XY:

0.0465

show subpopulations

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 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.:

AF XY:

0.0619

AC XY:

42713

AN XY:

689826

show subpopulations

African (AFR)

AF:

0.0110

AC:

346

AN:

31592

American (AMR)

AF:

0.0394

AC:

1405

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.0775

AC:

1949

AN:

25158

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35734

South Asian (SAS)

AF:

0.0152

AC:

1206

AN:

79218

European-Finnish (FIN)

AF:

0.0473

AC:

2333

AN:

49342

Middle Eastern (MID)

AF:

0.0593

AC:

338

AN:

5696

European-Non Finnish (NFE)

AF:

0.0714

AC:

76944

AN:

1078062

Other (OTH)

AF:

0.0569

AC:

3300

AN:

58024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

3913

7825

11738

15650

19563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2774

5548

8322

11096

13870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0474

AC:

7209

AN:

152248

Hom.:

254

Cov.:

AF XY:

0.0454

AC XY:

3380

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0112

AC:

467

AN:

41542

American (AMR)

AF:

0.0507

AC:

775

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0775

AC:

269

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5178

South Asian (SAS)

AF:

0.0155

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0431

AC:

457

AN:

10600

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0719

AC:

4895

AN:

68034

Other (OTH)

AF:

0.0479

AC:

101

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

343

686

1029

1372

1715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0611

Hom.:

675

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:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

PhyloP100

1.0

PROVEAN

Benign

-0.22

REVEL

Benign

0.062

Sift

Benign

0.23

Sift4G

Benign

0.29

Vest4

0.19

MPC

0.34

ClinPred

0.016

GERP RS

3.0

gMVP

0.28

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over