Variant 4-56656000-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_139211.5(HOPX):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,597,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HOPX
NM_139211.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOPX	NM_032495.6 linkuse as main transcript	c.55A>G	p.Met19Val	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.55A>G	p.Met19Val	missense_variant	3/4	5	NM_032495.6	ENSP00000396275.1		Q9BPY8-3

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151448

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000517

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151448

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73976

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Ambry Genetics

Jun 11, 2024

The c.55A>G (p.M19V) alteration is located in exon 3 (coding exon 2) of the HOPX gene. This alteration results from a A to G substitution at nucleotide position 55, causing the methionine (M) at amino acid position 19 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.26

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

Eigen

Benign

0.026

Eigen_PC

Benign

0.077

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.47

T;.;T;.;.;.;.;.;.;.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.74

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.061

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

Sift4G

Benign

0.19

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

Polyphen

0.28

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

Vest4

0.52

MutPred

1.0

.;Gain of glycosylation at S2 (P = 0.0914);.;Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);Gain of glycosylation at S2 (P = 0.0914);

MVP

0.34

MPC

0.32

ClinPred

0.96

GERP RS

4.8

Varity_R

0.87

gMVP

0.25

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