12-53939187-C-T

Variant names:

• chr12-53939187-C-T
• rs35956662
• NM_017410.3:c.281C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017410.3(HOXC13):​c.281C>T​(p.Thr94Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,369,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T94K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: HOXC13 NM_017410.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.02
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41174948).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017410.3. 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
	HOXC13	NM_017410.3	MANE Select	c.281C>T	p.Thr94Met	missense	Exon 1 of 2	NP_059106.2
	HOXC13-AS	NR_047507.1		n.173+284G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC13	ENST00000243056.5	TSL:1 MANE Select	c.281C>T	p.Thr94Met	missense	Exon 1 of 2	ENSP00000243056.3	P31276
	HOXC13-AS	ENST00000512916.3	TSL:3	n.222+284G>A		intron	N/A
	HOXC13-AS	ENST00000810609.1		n.181+284G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1369774 Hom.: 0 Cov.: 33 AF XY: 0.00000740 AC XY: 5 AN XY: 675532

African (AFR) AF: 0.00 AC: 0 AN: 29896

American (AMR) AF: 0.00 AC: 0 AN: 33060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24290

East Asian (EAS) AF: 0.00 AC: 0 AN: 34694

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5078

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1072162

Other (OTH) AF: 0.0000175 AC: 1 AN: 56998

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.055	T
Polyphen		0.95	P
Vest4		0.20
MutPred		0.35		Gain of catalytic residue at P99 (P = 0.001)
MVP		0.82
MPC		1.4
ClinPred		0.84	D
GERP RS		2.2
PromoterAI		0.040	Neutral
Varity_R		0.077
gMVP		0.26
Mutation Taster		=89/11	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: rs35956662; hg19: chr12-54332971;