NM_032495.6:c.199-1886G>A

Variant names:

• chr4-56650683-C-T
• rs76451666
• NM_032495.6:c.199-1886G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032495.6(HOPX):​c.199-1886G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,550,766 control chromosomes in the GnomAD database, including 3,351 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.047 (254 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3097 hom.)
• Consequence: HOPX NM_032495.6 intron
• Scores: Splicing: ADA: 0.7131
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 8 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015913248).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOPX	NM_032495.6	MANE Select	c.199-1886G>A		intron	N/A	NP_115884.4
	HOPX	NM_001145460.2		c.328G>A	p.Glu110Lys	missense splice_region	Exon 4 of 5	NP_001138932.1
	HOPX	NM_001145459.2		c.145-1886G>A		intron	N/A	NP_001138931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOPX	ENST00000420433.6	TSL:5 MANE Select	c.199-1886G>A		intron	N/A	ENSP00000396275.1
	HOPX	ENST00000317745.11	TSL:1	c.145-1886G>A		intron	N/A	ENSP00000315198.7
	HOPX	ENST00000337881.12	TSL:1	c.145-1886G>A		intron	N/A	ENSP00000337330.7

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7213 AN: 152130 Hom.: 255 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0484

GnomAD2 exomes AF: 0.0470 AC: 7400 AN: 157336 AF XY: 0.0465

Gnomad AFR exome AF: 0.00989

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0763

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0714

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0628 AC: 87823 AN: 1398518 Hom.: 3097 Cov.: 30 AF XY: 0.0619 AC XY: 42713 AN XY: 689826

African (AFR) AF: 0.0110 AC: 346 AN: 31592

American (AMR) AF: 0.0394 AC: 1405 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 1949 AN: 25158

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35734

South Asian (SAS) AF: 0.0152 AC: 1206 AN: 79218

European-Finnish (FIN) AF: 0.0473 AC: 2333 AN: 49342

Middle Eastern (MID) AF: 0.0593 AC: 338 AN: 5696

European-Non Finnish (NFE) AF: 0.0714 AC: 76944 AN: 1078062

Other (OTH) AF: 0.0569 AC: 3300 AN: 58024

GnomAD4 genome AF: 0.0474 AC: 7209 AN: 152248 Hom.: 254 Cov.: 32 AF XY: 0.0454 AC XY: 3380 AN XY: 74438

African (AFR) AF: 0.0112 AC: 467 AN: 41542

American (AMR) AF: 0.0507 AC: 775 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4824

European-Finnish (FIN) AF: 0.0431 AC: 457 AN: 10600

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0719 AC: 4895 AN: 68034

Other (OTH) AF: 0.0479 AC: 101 AN: 2108

Alfa AF: 0.0611 Hom.: 675

Bravo AF: 0.0470

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0641 AC: 247

ExAC AF: 0.0377 AC: 963

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.93
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.0
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.062
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Vest4		0.19
MPC		0.34
ClinPred		0.016	T
GERP RS		3.0
gMVP		0.28
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Benign	0.27
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: rs76451666; hg19: chr4-57516849;