12-54000553-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006897.3(HOXC9):c.365C>T(p.Ala122Val) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,545,436 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (57 hom.)
• Consequence: HOXC9 NM_006897.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.51

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]

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031582415).
• BP6: Variant 12-54000553-C-T is Benign according to our data. Variant chr12-54000553-C-T is described in ClinVar as [Benign]. Clinvar id is 776712.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXC9	NM_006897.3	c.365C>T	p.Ala122Val	missense_variant	1/2	ENST00000303450.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXC9	ENST00000303450.5	c.365C>T	p.Ala122Val	missense_variant	1/2	1	NM_006897.3	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2296 AN: 152230 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00455 AC: 651 AN: 143122 Hom.: 13 AF XY: 0.00353 AC XY: 282 AN XY: 79884

Gnomad AFR exome AF: 0.0664

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000462

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00189 AC: 2628 AN: 1393090 Hom.: 57 Cov.: 31 AF XY: 0.00175 AC XY: 1206 AN XY: 689504

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000248

Gnomad4 FIN exome AF: 0.0000275

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.0151 AC: 2301 AN: 152346 Hom.: 52 Cov.: 33 AF XY: 0.0144 AC XY: 1071 AN XY: 74498

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00584 Hom.: 7

Bravo AF: 0.0175

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0381 AC: 117

ESP6500EA AF: 0.000913 AC: 6

ExAC AF: 0.00389 AC: 414

Asia WGS AF: 0.00549 AC: 19 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.33	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.034	B;B
Vest4		0.56
MVP		0.92
MPC		0.89
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.20

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: rs11829948; hg19: chr12-54394337;