chr12-54054322-A-C

Position:

• chr12-54054322-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153633.3(HOXC4):​c.400A>C​(p.Ile134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency: Genomes: not found (cov: 28)
• Consequence: HOXC4 NM_153633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94

Genes affected

HOXC4 (HGNC:5126): (homeobox C4) 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, HOXC4, is one of several homeobox 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. Two alternatively spliced variants that encode the same protein have been described for HOXC4. Transcript variant one includes the shared exon, and transcript variant two includes only gene-specific exons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2351115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXC4	NM_153633.3	c.400A>C	p.Ile134Leu	missense_variant	1/2	ENST00000430889.3	NP_705897.1
HOXC4	NM_014620.6	c.400A>C	p.Ile134Leu	missense_variant	3/4		NP_055435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXC4	ENST00000430889.3	c.400A>C	p.Ile134Leu	missense_variant	1/2	1	NM_153633.3	ENSP00000399808.2
HOXC4	ENST00000303406.4	c.400A>C	p.Ile134Leu	missense_variant	3/4	1		ENSP00000305973.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.083	B;B
Vest4		0.30
MutPred		0.38		Gain of catalytic residue at V135 (P = 9e-04);Gain of catalytic residue at V135 (P = 9e-04);
MVP		0.86
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.44
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75256744; hg19: chr12-54448106;