12-53939186-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017410.3(HOXC13):c.280A>G(p.Thr94Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,521,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T94K) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

HOXC13
NM_017410.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

HOXC13 (HGNC:5125): (homeobox C13) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The product of this gene may play a role in the development of hair, nail, and filiform papilla. [provided by RefSeq, Jul 2008]

HOXC13 links:

HOXC13-AS (HGNC:43753): (HOXC13 antisense RNA)

HOXC13-AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07131183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC13	NM_017410.3 link	c.280A>G	p.Thr94Ala	missense_variant	Exon 1 of 2	ENST00000243056.5	NP_059106.2	P31276
HOXC13-AS	NR_047507.1 link	n.173+285T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC13	ENST00000243056.5 link	c.280A>G	p.Thr94Ala	missense_variant	Exon 1 of 2	1	NM_017410.3	ENSP00000243056.3		P31276
HOXC13-AS	ENST00000512916.2 link	n.173+285T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000424

AC:

AN:

117818

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

65298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000903

Gnomad OTH exome

AF:

0.000282

GnomAD4 exome

AF:

0.0000694

AC:

AN:

1369696

Hom.:

Cov.:

AF XY:

0.0000622

AC XY:

AN XY:

675530

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000121

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:

0.0000830

Gnomad4 OTH exome

AF:

0.0000351

GnomAD4 genome

AF:

0.000125

AC:

AN:

151778

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000476

Bravo

AF:

0.0000982

ExAC

AF:

0.0000235

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280A>G (p.T94A) alteration is located in exon 1 (coding exon 1) of the HOXC13 gene. This alteration results from a A to G substitution at nucleotide position 280, causing the threonine (T) at amino acid position 94 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

HOXC13-related disorder

Uncertain:1

Jan 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HOXC13 c.280A>G variant is predicted to result in the amino acid substitution p.Thr94Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.037

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.70

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.35

REVEL

Benign

0.040

Sift

Benign

0.15

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.060

MutPred

0.29

Gain of catalytic residue at P99 (P = 0.001);

MVP

0.39

MPC

0.73

ClinPred

0.037

GERP RS

0.47

Varity_R

0.048

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over