Genetic Variant NM_017410.3:c.281C>A (chr12-53939187-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017410.3(HOXC13):c.281C>A(p.Thr94Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00334 in 1,522,010 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T94A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 16 hom. )

Consequence

HOXC13
NM_017410.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.02

Publications

2 publications found

Variant links:

Genes affected

HOXC13 (HGNC:5125): (homeobox C13) 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 may play a role in the development of hair, nail, and filiform papilla. [provided by RefSeq, Jul 2008]

HOXC13 links:

HOXC13-AS (HGNC:43753): (HOXC13 antisense RNA)

HOXC13-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008624017).

BP6

Variant 12-53939187-C-A is Benign according to our data. Variant chr12-53939187-C-A is described in ClinVar as Benign. ClinVar VariationId is 1588495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017410.3. 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
	HOXC13	NM_017410.3	MANE Select	c.281C>A	p.Thr94Lys	missense	Exon 1 of 2	NP_059106.2
	HOXC13-AS	NR_047507.1		n.173+284G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOXC13	ENST00000243056.5	TSL:1 MANE Select	c.281C>A	p.Thr94Lys	missense	Exon 1 of 2	ENSP00000243056.3	P31276
HOXC13-AS	ENST00000512916.3	TSL:3	n.222+284G>T		intron	N/A
HOXC13-AS	ENST00000810609.1		n.181+284G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

390

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00744

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00351

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00392

AC:

461

AN:

117550

AF XY:

0.00438

show subpopulations

Gnomad AFR exome

AF:

0.000812

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000144

Gnomad NFE exome

AF:

0.00426

Gnomad OTH exome

AF:

0.00367

GnomAD4 exome

AF:

0.00342

AC:

4689

AN:

1369764

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

2386

AN XY:

675528

show subpopulations

African (AFR)

AF:

0.000569

AC:

AN:

29896

American (AMR)

AF:

0.00191

AC:

AN:

33060

Ashkenazi Jewish (ASJ)

AF:

0.00967

AC:

235

AN:

24290

East Asian (EAS)

AF:

0.00

AC:

AN:

34694

South Asian (SAS)

AF:

0.00589

AC:

454

AN:

77076

European-Finnish (FIN)

AF:

0.000110

AC:

AN:

36516

Middle Eastern (MID)

AF:

0.00670

AC:

AN:

5078

European-Non Finnish (NFE)

AF:

0.00335

AC:

3587

AN:

1072156

Other (OTH)

AF:

0.00518

AC:

295

AN:

56998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

265

530

794

1059

1324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00257

AC:

391

AN:

152246

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41550

American (AMR)

AF:

0.00268

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00745

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00353

AC:

240

AN:

67988

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000385

AC:

ESP6500EA

AF:

0.00280

AC:

ExAC

AF:

0.00162

AC:

138

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.089

Eigen

Benign

0.00060

Eigen_PC

Benign

-0.0037

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

PhyloP100

4.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.0

REVEL

Benign

0.066

Sift

Uncertain

0.026

Sift4G

Benign

0.48

Polyphen

0.48

Vest4

0.27

MVP

0.81

MPC

1.1

ClinPred

0.027

GERP RS

2.2

PromoterAI

0.060

Neutral

(source)

Varity_R

0.15

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over