rs4759315

Variant names:

• chr12-53973277-T-G
• rs4759315
• NM_014212.4:c.36T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_014212.4(HOXC11):​c.36T>G​(p.Ser12Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,612,844 control chromosomes in the GnomAD database, including 806,272 homozygotes. 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: 𝑓 1.0 (76054 hom., cov: 31)
  • Exomes 𝑓: 1.0 (730218 hom.)
• Consequence: HOXC11 NM_014212.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.872
• Publications: 12 publications found

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]

ENSG00000293681 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP7: Synonymous conserved (PhyloP=0.872 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014212.4. 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
	HOXC11	NM_014212.4	MANE Select	c.36T>G	p.Ser12Ser	synonymous	Exon 1 of 2	NP_055027.1	O43248
	HOTAIR	NR_186241.1	MANE Select	n.57+1621A>C		intron	N/A
	HOTAIR	NR_047517.2		n.57+1621A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC11	ENST00000546378.1	TSL:1 MANE Select	c.36T>G	p.Ser12Ser	synonymous	Exon 1 of 2	ENSP00000446680.1	O43248
	HOTAIR	ENST00000424518.6	TSL:5 MANE Select	n.57+1621A>C		intron	N/A
	HOXC11	ENST00000243082.4	TSL:3	c.36T>G	p.Ser12Ser	synonymous	Exon 1 of 2	ENSP00000243082.4	J3KMZ0

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152070 AN: 152148 Hom.: 75996 Cov.: 31

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 249845 AN: 249880 AF XY: 1.00

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1460507 AN: 1460578 Hom.: 730218 Cov.: 59 AF XY: 1.00 AC XY: 726644 AN XY: 726678

African (AFR) AF: 0.998 AC: 33427 AN: 33478

American (AMR) AF: 1.00 AC: 44698 AN: 44704

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26092 AN: 26092

East Asian (EAS) AF: 1.00 AC: 39695 AN: 39696

South Asian (SAS) AF: 1.00 AC: 86216 AN: 86216

European-Finnish (FIN) AF: 1.00 AC: 52515 AN: 52516

Middle Eastern (MID) AF: 1.00 AC: 5762 AN: 5762

European-Non Finnish (NFE) AF: 1.00 AC: 1111746 AN: 1111748

Other (OTH) AF: 1.00 AC: 60356 AN: 60366

GnomAD4 genome AF: 0.999 AC: 152187 AN: 152266 Hom.: 76054 Cov.: 31 AF XY: 1.00 AC XY: 74411 AN XY: 74446

African (AFR) AF: 0.998 AC: 41473 AN: 41552

American (AMR) AF: 1.00 AC: 15312 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5134 AN: 5134

South Asian (SAS) AF: 1.00 AC: 4814 AN: 4814

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68030 AN: 68030

Other (OTH) AF: 1.00 AC: 2116 AN: 2116

Alfa AF: 1.00 Hom.: 14360

Bravo AF: 0.999

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.87
PromoterAI		-0.029	Neutral
Mutation Taster		=91/9	polymorphism (auto)

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: rs4759315; hg19: chr12-54367061; COSMIC: COSV54533762; COSMIC: COSV54533762;