chr12-54000613-T-C

Variant names:

• chr12-54000613-T-C
• rs750168236
• NM_006897.3:c.425T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_006897.3(HOXC9):​c.425T>C​(p.Met142Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000036 in 1,388,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HOXC9 NM_006897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.00

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25285476).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC9	NM_006897.3	c.425T>C	p.Met142Thr	missense_variant	Exon 1 of 2	ENST00000303450.5	NP_008828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC9	ENST00000303450.5	c.425T>C	p.Met142Thr	missense_variant	Exon 1 of 2	1	NM_006897.3	ENSP00000302836.4
ENSG00000273049	ENST00000513209.1	c.166+14603T>C		intron_variant	Intron 1 of 1	3		ENSP00000476742.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000360 AC: 5 AN: 1388216 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 686330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.53	.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.23	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.25	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.64	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0010	B;B
Vest4		0.34
MutPred		0.39		Gain of catalytic residue at Y143 (P = 0.0018);Gain of catalytic residue at Y143 (P = 0.0018);
MVP		0.91
MPC		0.97
ClinPred		0.53	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33

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: rs750168236; hg19: chr12-54394397;