12-53973307-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014212.4(HOXC11):​c.66C>G​(p.Phe22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HOXC11
NM_014212.4 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXC11NM_014212.4 linkc.66C>G p.Phe22Leu missense_variant Exon 1 of 2 ENST00000546378.1 NP_055027.1 O43248

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXC11ENST00000546378.1 linkc.66C>G p.Phe22Leu missense_variant Exon 1 of 2 1 NM_014212.4 ENSP00000446680.1 O43248
HOXC11ENST00000243082.4 linkc.66C>G p.Phe22Leu missense_variant Exon 1 of 2 3 ENSP00000243082.4 J3KMZ0
HOTAIRENST00000424518.5 linkn.59+1591G>C intron_variant Intron 1 of 6 5
HOTAIRENST00000455246.6 linkn.59+1591G>C intron_variant Intron 1 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251012
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461688
Hom.:
0
Cov.:
40
AF XY:
0.00000688
AC XY:
5
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.66C>G (p.F22L) alteration is located in exon 1 (coding exon 1) of the HOXC11 gene. This alteration results from a C to G substitution at nucleotide position 66, causing the phenylalanine (F) at amino acid position 22 to be replaced by a leucine (L). 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
0.78
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
0.12
Eigen_PC
Benign
0.094
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.76
T;T
M_CAP
Uncertain
0.25
D
MetaRNN
Uncertain
0.60
D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
1.4
L;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Uncertain
0.48
Sift
Benign
0.031
D;D
Sift4G
Benign
0.093
T;D
Polyphen
0.97
D;.
Vest4
0.80
MutPred
0.33
Gain of catalytic residue at S27 (P = 0.0143);Gain of catalytic residue at S27 (P = 0.0143);
MVP
0.96
ClinPred
0.97
D
GERP RS
3.2
Varity_R
0.57
gMVP
0.16

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.

Other links and lift over

dbSNP: rs767025016; hg19: chr12-54367091; API