4-56655888-G-A

Position:

• chr4-56655888-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_032495.6(HOPX):​c.167C>T​(p.Ala56Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,590 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HOPX NM_032495.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.35

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• BP6: Variant 4-56655888-G-A is Benign according to our data. Variant chr4-56655888-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 496485.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOPX	NM_032495.6	c.167C>T	p.Ala56Val	missense_variant	3/4	ENST00000420433.6
LOC124900708	XR_007058129.1	n.302+296G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOPX	ENST00000420433.6	c.167C>T	p.Ala56Val	missense_variant	3/4	5	NM_032495.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000368 AC: 9 AN: 244842 Hom.: 0 AF XY: 0.0000452 AC XY: 6 AN XY: 132790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459590 Hom.: 0 Cov.: 34 AF XY: 0.00000827 AC XY: 6 AN XY: 725936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 24, 2017

Variant summary: The HOPX c.167C>T (p.Ala56Val) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/104066 control chromosomes at a frequency of 0.0000288, which is approximately equivalent to the estimated maximal expected allele frequency of a pathogenic HOPX variant (0.000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;.;D;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;D;D;D;D;D;D;D;.;D
Vest4		0.63
MutPred		0.37		.;Loss of disorder (P = 0.0823);.;Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);Loss of disorder (P = 0.0823);
MVP		0.91
MPC		0.73
ClinPred		0.50	D
GERP RS		3.8
Varity_R		0.36
gMVP		0.36

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: rs752905777; hg19: chr4-57522054; COSMIC: COSV100497028; COSMIC: COSV100497028;