4-56655924-T-C

Position:

• chr4-56655924-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032495.6(HOPX):​c.131A>G​(p.Lys44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HOPX NM_032495.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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]

LOC124900708 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28803992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOPX	NM_032495.6	c.131A>G	p.Lys44Arg	missense_variant	3/4	ENST00000420433.6	NP_115884.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOPX	ENST00000420433.6	c.131A>G	p.Lys44Arg	missense_variant	3/4	5	NM_032495.6	ENSP00000396275.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459604 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.131A>G (p.K44R) 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 131, causing the lysine (K) at amino acid position 44 to be replaced by an arginine (R). 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
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	.;D;.;D;D;D;D;D;D;D;.;D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.80	T;.;T;.;.;.;.;.;.;.;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.37
Sift	Benign	0.15	T;T;D;T;T;T;T;T;T;T;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0010	.;B;.;B;B;B;B;B;B;B;.;B
Vest4		0.31
MutPred		0.44		.;Loss of methylation at K26 (P = 0.0083);.;Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);Loss of methylation at K26 (P = 0.0083);
MVP		0.85
MPC		0.51
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.12
gMVP		0.28

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: rs372412335; hg19: chr4-57522090;