chr12-53973334-C-A

Variant names:

• chr12-53973334-C-A
• NM_014212.4:c.93C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014212.4(HOXC11):​c.93C>A​(p.Asn31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOXC11 NM_014212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.649
• Publications: 0 publications found

Genes affected

HOXC11 (HGNC:5123): (homeobox C11) 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 binds to a promoter element of the lactase-phlorizin hydrolase. It also may play a role in early intestinal development. An alternatively spliced variant encoding a shorter isoform has been described but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

HOTAIR (HGNC:33510): (HOX transcript antisense RNA) This gene is located within the Homeobox C (HOXC) gene cluster on chromosome 12 and is co-expressed with the HOXC genes. It functions through an RNA product, which binds lysine specific demethylase 1 (LSD1) and Polycomb repressive complex 2 (PRC2), and serves as a scaffold to assemble these regulators at the HOXD gene cluster, thereby promoting epigenetic repression of HOXD. This gene is highly expressed in multiple tumors. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Feb 2019]

ENSG00000293681 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014212.4. 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
	HOXC11	NM_014212.4	MANE Select	c.93C>A	p.Asn31Lys	missense	Exon 1 of 2	NP_055027.1	O43248
	HOTAIR	NR_186241.1	MANE Select	n.57+1564G>T		intron	N/A
	HOTAIR	NR_047517.2		n.57+1564G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC11	ENST00000546378.1	TSL:1 MANE Select	c.93C>A	p.Asn31Lys	missense	Exon 1 of 2	ENSP00000446680.1	O43248
	HOTAIR	ENST00000424518.6	TSL:5 MANE Select	n.57+1564G>T		intron	N/A
	HOXC11	ENST00000243082.4	TSL:3	c.93C>A	p.Asn31Lys	missense	Exon 1 of 2	ENSP00000243082.4	J3KMZ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.65
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.39		Gain of catalytic residue at N31 (P = 0)
MVP		0.96
ClinPred		0.99	D
GERP RS		1.6
PromoterAI		-0.032	Neutral
Varity_R		0.83
gMVP		0.48
Mutation Taster		=48/52	disease causing

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

hg19: chr12-54367118;