rs483353075

Positions:

chr4-56655931-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032495.6(HOPX):c.124G>A(p.Val42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,611,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

HOPX
NM_032495.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

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:

LOC124900708 (HGNC:):

LOC124900708 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02616775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOPX	NM_032495.6 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	3/4	ENST00000420433.6	NP_115884.4	Q9BPY8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOPX	ENST00000420433.6 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	3/4	5	NM_032495.6	ENSP00000396275.1		Q9BPY8-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000774

AC:

AN:

245632

Hom.:

AF XY:

0.0000601

AC XY:

AN XY:

133174

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00151

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1459614

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

725938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 07, 2010

The Val24Ile variant has not been reported in the literature. It was absent from 338 Caucasian or 376 Black control chromosomes, excluding the possibility that it is a common variant in these populations (LMM, unpublished data). Valine at p osition 24 is conserved in mammals and chicken but one species (pufferfish) natu rally carries isoleucine (Ile), raising the possibility that the change observed in this individual may be tolerated. In addition, the Val24Ile variant segregat es in this family along with a second, likely pathogenic variant, which decrease s the likelihood that the Val24Ile variant is disease causing in isolation. How ever, we cannot determine its clinical significance without additional studies. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.54

.;D;.;D;D;D;D;D;D;D;.;D

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.86

D;.;D;.;.;.;.;.;.;.;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.026

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.45

N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.41

T;T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.066

T;T;D;T;T;T;T;T;T;T;T;T

Polyphen

0.011

.;B;.;B;B;B;B;B;B;B;.;B

Vest4

0.30

MutPred

0.32

.;Loss of ubiquitination at K23 (P = 0.0683);.;Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);Loss of ubiquitination at K23 (P = 0.0683);

MVP

0.30

MPC

0.33

ClinPred

0.095

GERP RS

3.8

Varity_R

0.062

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over