4-56655909-G-T

Position:

• chr4-56655909-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032495.6(HOPX):​c.146C>A​(p.Thr49Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOPX NM_032495.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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 2 ACMG points.

• 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	c.146C>A	p.Thr49Asn	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.146C>A	p.Thr49Asn	missense_variant	3/4	5	NM_032495.6	ENSP00000396275.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Oct 07, 2024

The c.146C>A (p.T49N) alteration is located in exon 3 (coding exon 2) of the HOPX gene. This alteration results from a C to A substitution at nucleotide position 146, causing the threonine (T) at amino acid position 49 to be replaced by an asparagine (N). 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	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	.;D;.;D;D;D;D;D;D;D;.;D
Eigen	Benign	0.028
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;.;D;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.27	.;B;.;B;B;B;B;B;B;B;.;B
Vest4		0.54
MutPred		0.32		.;Loss of glycosylation at S30 (P = 0.0946);.;Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);Loss of glycosylation at S30 (P = 0.0946);
MVP		0.91
MPC		0.74
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.35
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57522075;