12-53975232-G-C

Position:

• chr12-53975232-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014212.4(HOXC11):​c.734G>C​(p.Arg245Pro) variant causes a missense change involving the alteration of a 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: 30)
• Consequence: HOXC11 NM_014212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXC11	NM_014212.4	c.734G>C	p.Arg245Pro	missense_variant	2/2	ENST00000546378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXC11	ENST00000546378.1	c.734G>C	p.Arg245Pro	missense_variant	2/2	1	NM_014212.4	P1
HOXC11	ENST00000243082.4	c.738G>C	p.Pro246=	synonymous_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.734G>C (p.R245P) alteration is located in exon 2 (coding exon 2) of the HOXC11 gene. This alteration results from a G to C substitution at nucleotide position 734, causing the arginine (R) at amino acid position 245 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.58		Loss of MoRF binding (P = 0.0053);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-54369016;