chr12-53999990-G-T

Variant names:

• chr12-53999990-G-T
• rs12817092
• ENST00000513209.1:c.166+13980G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000513209.1(ENSG00000273049):​c.166+13980G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 458,270 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: 29)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ENSG00000273049 ENST00000513209.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 9 publications found

Genes affected

ENSG00000273049 (HGNC:):

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]

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]

HOXC-AS1 (HGNC:43749): (HOXC cluster antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000513209.1. 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
	HOXC-AS1	NR_047504.1		n.21C>A		non_coding_transcript_exon	Exon 1 of 2
	HOXC9	NM_006897.3	MANE Select	c.-199G>T		upstream_gene	N/A	NP_008828.1	P31274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000273049	ENST00000513209.1	TSL:3	c.166+13980G>T		intron	N/A	ENSP00000476742.1	V9GYH0
	HOXC9	ENST00000508190.1	TSL:3	c.-57-142G>T		intron	N/A	ENSP00000423861.1	P31274
	HOXC6	ENST00000509328.1	TSL:3	c.-73+4974G>T		intron	N/A	ENSP00000423898.1	D6RC34

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000218 AC: 1 AN: 458270 Hom.: 0 Cov.: 5 AF XY: 0.00000415 AC XY: 1 AN XY: 240846

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12042

American (AMR) AF: 0.00 AC: 0 AN: 16758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13580

East Asian (EAS) AF: 0.00 AC: 0 AN: 29400

South Asian (SAS) AF: 0.00 AC: 0 AN: 42508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2000

European-Non Finnish (NFE) AF: 0.00000349 AC: 1 AN: 286614

Other (OTH) AF: 0.00 AC: 0 AN: 26028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.3
DANN	Benign	0.76
PhyloP100		-1.5
PromoterAI		-0.060	Neutral

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: rs12817092; hg19: chr12-54393774;