12-53939186-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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

ACMG classification

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/exons	MANE	UniProt
HOXC13	NM_017410.3	c.280A>G	p.Thr94Ala	missense_variant	1/2	ENST00000243056.5
HOXC13-AS	NR_047507.1	n.173+285T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXC13	ENST00000243056.5	c.280A>G	p.Thr94Ala	missense_variant	1/2	1	NM_017410.3	P1
HOXC13-AS	ENST00000512916.2	n.173+285T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151664 Hom.: 0 Cov.: 32

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: 5 AN: 117818 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65298

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: 95 AN: 1369696 Hom.: 0 Cov.: 33 AF XY: 0.0000622 AC XY: 42 AN XY: 675530

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: 19 AN: 151778 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74196

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: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

HOXC13-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

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	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	21
Dann	Benign	0.83
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.70	N
MutationTaster	Benign	0.66	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.040
Sift	Benign	0.15	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.29		Gain of catalytic residue at P99 (P = 0.001);
MVP		0.39
MPC		0.73
ClinPred		0.037	T
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

Other links and lift over

dbSNP: rs767074923; hg19: chr12-54332970;