4-56655931-C-G

Variant names:

• chr4-56655931-C-G
• rs483353075
• NM_032495.6:c.124G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032495.6(HOPX):​c.124G>C​(p.Val42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V42I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HOPX NM_032495.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• Publications: 0 publications found

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]

ENSG00000310269 (HGNC:58797):

LOC124900708 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1502198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032495.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOPX	NM_032495.6	MANE Select	c.124G>C	p.Val42Leu	missense	Exon 3 of 4	NP_115884.4
	HOPX	NM_001145460.2		c.124G>C	p.Val42Leu	missense	Exon 3 of 5	NP_001138932.1	Q9BPY8-4
	HOPX	NM_001145459.2		c.70G>C	p.Val24Leu	missense	Exon 2 of 3	NP_001138931.1	Q9BPY8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOPX	ENST00000420433.6	TSL:5 MANE Select	c.124G>C	p.Val42Leu	missense	Exon 3 of 4	ENSP00000396275.1	Q9BPY8-3
	HOPX	ENST00000317745.11	TSL:1	c.70G>C	p.Val24Leu	missense	Exon 2 of 3	ENSP00000315198.7	Q9BPY8-1
	HOPX	ENST00000337881.12	TSL:1	c.70G>C	p.Val24Leu	missense	Exon 2 of 3	ENSP00000337330.7	Q9BPY8-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459614 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725938

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111094

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.045
Sift	Benign	0.17	T
Sift4G	Uncertain	0.039	D
Polyphen		0.0030	B
Vest4		0.28
MutPred		0.35		Loss of methylation at K23 (P = 0.0532)
MVP		0.41
MPC		0.39
ClinPred		0.92	D
GERP RS		3.8
PromoterAI		-0.087	Neutral
Varity_R		0.18
gMVP		0.39
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs483353075; hg19: chr4-57522097;