Genetic Variant HOXC4:p.Ile134Val (chr12-54054322-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_153633.3(HOXC4):c.400A>G(p.Ile134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,567,228 control chromosomes in the GnomAD database, including 24,934 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1601 hom., cov: 28)

Exomes 𝑓: 0.18 ( 23333 hom. )

Consequence

HOXC4
NM_153633.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

17 publications found

Variant links:

Genes affected

HOXC4 (HGNC:5126): (homeobox C4) 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, HOXC4, is one of several homeobox 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. Two alternatively spliced variants that encode the same protein have been described for HOXC4. Transcript variant one includes the shared exon, and transcript variant two includes only gene-specific exons. [provided by RefSeq, Jul 2008]

HOXC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012289286).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC4	NM_153633.3 link	c.400A>G	p.Ile134Val	missense_variant	Exon 1 of 2	ENST00000430889.3	NP_705897.1	P09017A0A024RB51Q86TF7
HOXC4	NM_014620.6 link	c.400A>G	p.Ile134Val	missense_variant	Exon 3 of 4		NP_055435.2	P09017A0A024RB51Q86TF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC4	ENST00000430889.3 link	c.400A>G	p.Ile134Val	missense_variant	Exon 1 of 2	1	NM_153633.3	ENSP00000399808.2		P09017
HOXC4	ENST00000303406.4 link	c.400A>G	p.Ile134Val	missense_variant	Exon 3 of 4	1		ENSP00000305973.4		P09017

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

19461

AN:

142272

Hom.:

1595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0423

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.0394

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.183

Gnomad OTH

AF:

0.165

GnomAD2 exomes

AF:

0.153

AC:

36106

AN:

236348

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.0880

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.184

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.176

AC:

250884

AN:

1424876

Hom.:

23333

Cov.:

AF XY:

0.179

AC XY:

126595

AN XY:

708514

show subpopulations

African (AFR)

AF:

0.0352

AC:

1108

AN:

31518

American (AMR)

AF:

0.0946

AC:

3914

AN:

41388

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

5814

AN:

24566

East Asian (EAS)

AF:

0.0350

AC:

1307

AN:

37352

South Asian (SAS)

AF:

0.239

AC:

20273

AN:

84982

European-Finnish (FIN)

AF:

0.134

AC:

6658

AN:

49518

Middle Eastern (MID)

AF:

0.222

AC:

1218

AN:

5496

European-Non Finnish (NFE)

AF:

0.183

AC:

200231

AN:

1092160

Other (OTH)

AF:

0.179

AC:

10361

AN:

57896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

10045

20090

30134

40179

50224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6960

13920

20880

27840

34800

<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:

0.137

AC:

19485

AN:

142352

Hom.:

1601

Cov.:

AF XY:

0.137

AC XY:

9481

AN XY:

69136

show subpopulations

African (AFR)

AF:

0.0429

AC:

1615

AN:

37670

American (AMR)

AF:

0.134

AC:

1913

AN:

14224

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

804

AN:

3398

East Asian (EAS)

AF:

0.0396

AC:

175

AN:

4424

South Asian (SAS)

AF:

0.246

AC:

1075

AN:

4368

European-Finnish (FIN)

AF:

0.136

AC:

1234

AN:

9090

Middle Eastern (MID)

AF:

0.291

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.183

AC:

12091

AN:

66036

Other (OTH)

AF:

0.167

AC:

332

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

792

1585

2377

3170

3962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.163

Hom.:

7202

Bravo

AF:

0.123

TwinsUK

AF:

0.149

AC:

554

ALSPAC

AF:

0.175

AC:

675

ESP6500AA

AF:

0.0418

AC:

184

ESP6500EA

AF:

0.175

AC:

1507

ExAC

AF:

0.154

AC:

18597

Asia WGS

AF:

0.138

AC:

480

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.60

.;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.56

N;N

PhyloP100

1.9

PrimateAI

Benign

0.45

PROVEAN

Benign

0.45

N;N

REVEL

Uncertain

0.36

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.036

ClinPred

0.011

GERP RS

4.3

PromoterAI

0.020

Neutral

(source)

Varity_R

0.093

gMVP

0.15

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over