12-53973449-G-A

Position:

• chr12-53973449-G-A

Variant summary

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

The NM_014212.4(HOXC11):​c.208G>A​(p.Val70Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HOXC11 NM_014212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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]

ACMG classification

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/exons	MANE	UniProt
HOXC11	NM_014212.4	c.208G>A	p.Val70Ile	missense_variant	1/2	ENST00000546378.1
HOTAIR	NR_047517.1	n.59+1449C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXC11	ENST00000546378.1	c.208G>A	p.Val70Ile	missense_variant	1/2	1	NM_014212.4	P1
HOTAIR	ENST00000424518.5	n.59+1449C>T		intron_variant, non_coding_transcript_variant		5
HOXC11	ENST00000243082.4	c.208G>A	p.Val70Ile	missense_variant	1/2	3
HOTAIR	ENST00000455246.6	n.59+1449C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 31

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

Feb 27, 2024

The c.208G>A (p.V70I) alteration is located in exon 1 (coding exon 1) of the HOXC11 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the valine (V) at amino acid position 70 to be replaced by an isoleucine (I). 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	Benign	0.14
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.99	D;.
Vest4		0.55
MutPred		0.25		Gain of catalytic residue at P68 (P = 5e-04);Gain of catalytic residue at P68 (P = 5e-04);
MVP		0.85
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.32

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: rs956711637; hg19: chr12-54367233;