Genetic Variant NM_006897.3:c.389G>A (chr12-54000577-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006897.3(HOXC9):c.389G>A(p.Cys130Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,382,342 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C130F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HOXC9
NM_006897.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.95

Publications

0 publications found

Variant links:

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]

HOXC9 links:

ENSG00000273049 (HGNC:):

ENSG00000273049 links:

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]

HOXC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC9	NM_006897.3 link	c.389G>A	p.Cys130Tyr	missense_variant	Exon 1 of 2	ENST00000303450.5	NP_008828.1	P31274A0A024RAZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC9	ENST00000303450.5 link	c.389G>A	p.Cys130Tyr	missense_variant	Exon 1 of 2	1	NM_006897.3	ENSP00000302836.4		P31274
ENSG00000273049	ENST00000513209.1 link	c.166+14567G>A		intron_variant	Intron 1 of 1	3		ENSP00000476742.1		V9GYH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000759

AC:

AN:

131734

AF XY:

0.0000136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1382342

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30838

American (AMR)

AF:

0.00

AC:

AN:

31852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24704

East Asian (EAS)

AF:

0.00

AC:

AN:

35948

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5066

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080290

Other (OTH)

AF:

0.00

AC:

AN:

57510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

.;T

M_CAP

Pathogenic

0.64

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

6.9

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.77

P;P

Vest4

0.38

MutPred

0.64

Gain of phosphorylation at C130 (P = 0.0081);Gain of phosphorylation at C130 (P = 0.0081);

MVP

1.0

MPC

1.6

ClinPred

0.94

GERP RS

4.0

PromoterAI

0.058

Neutral

(source)

Varity_R

0.79

Mutation Taster

=49/51

disease causing

(source)

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

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NM_006897.3:c.389G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over