12-54000321-C-G

Variant names:

• chr12-54000321-C-G
• rs1350644175
• NM_006897.3:c.133C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006897.3(HOXC9):​c.133C>G​(p.Pro45Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P45T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXC9 NM_006897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 1 publications found

Genes affected

HOXC9 (HGNC:5130): (homeobox C9) 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. [provided by RefSeq, Jul 2008]

ENSG00000273049 (HGNC:):

HOXC6 (HGNC:5128): (homeobox C6) This gene belongs to the homeobox family, members of which 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, HOXC6, is one of several HOXC genes located in a cluster on chromosome 12. Three genes, HOXC5, HOXC4 and HOXC6, share a 5' non-coding exon. Transcripts may include the shared exon spliced to the gene-specific exons, or they may include only the gene-specific exons. Alternatively spliced transcript variants encoding different isoforms have been identified for HOXC6. Transcript variant two includes the shared exon, and transcript variant one includes only gene-specific exons. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16780224).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006897.3. 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
	HOXC9	NM_006897.3	MANE Select	c.133C>G	p.Pro45Ala	missense	Exon 1 of 2	NP_008828.1	P31274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC9	ENST00000303450.5	TSL:1 MANE Select	c.133C>G	p.Pro45Ala	missense	Exon 1 of 2	ENSP00000302836.4	P31274
	ENSG00000273049	ENST00000513209.1	TSL:3	c.166+14311C>G		intron	N/A	ENSP00000476742.1	V9GYH0
	HOXC9	ENST00000508190.1	TSL:3	c.133C>G	p.Pro45Ala	missense	Exon 2 of 3	ENSP00000423861.1	P31274

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T
Sift4G	Benign	0.47	T
Polyphen		0.024	B
Vest4		0.31
MutPred		0.49		Gain of catalytic residue at F50 (P = 0.0044)
MVP		0.97
MPC		0.80
ClinPred		0.39	T
GERP RS		3.9
PromoterAI		0.085	Neutral
Varity_R		0.15
Mutation Taster		=36/64	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

dbSNP: rs1350644175; hg19: chr12-54394105;