Genetic Variant HOXD1:c.653-125T>C (chr2-176189683-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_024501.3(HOXD1):c.653-125T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,600,720 control chromosomes in the GnomAD database, including 66,377 homozygotes. 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: 𝑓 0.31 ( 7851 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58526 hom. )

Consequence

HOXD1
NM_024501.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.390

Publications

15 publications found

Variant links:

Genes affected

HOXD1 (HGNC:5132): (homeobox D1) This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. This nuclear protein functions as a sequence-specific transcription factor that is involved in differentiation and limb development. Mutations in this gene have been associated with severe developmental defects on the anterior-posterior (a-p) limb axis. [provided by RefSeq, Jul 2008]

HOXD1 links:

ENSG00000279160 (HGNC:):

ENSG00000279160 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD1	NM_024501.3 link	c.653-125T>C		intron_variant	Intron 1 of 1	ENST00000331462.6	NP_078777.1	Q9GZZ0Q96CA4
HOXD1	XM_047444086.1 link	c.785+2T>C		splice_donor_variant, intron_variant	Intron 2 of 2		XP_047300042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD1	ENST00000331462.6 link	c.653-125T>C		intron_variant	Intron 1 of 1	1	NM_024501.3	ENSP00000328598.4		Q9GZZ0
ENSG00000279160	ENST00000623777.1 link	n.*236A>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46648

AN:

151892

Hom.:

7827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.0211

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.280

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.245

AC:

54724

AN:

222958

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.0231

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.295

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.276

AC:

399171

AN:

1448710

Hom.:

58526

Cov.:

AF XY:

0.272

AC XY:

196108

AN XY:

719906

show subpopulations

African (AFR)

AF:

0.434

AC:

14389

AN:

33176

American (AMR)

AF:

0.168

AC:

7065

AN:

41940

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8870

AN:

25884

East Asian (EAS)

AF:

0.0149

AC:

587

AN:

39298

South Asian (SAS)

AF:

0.166

AC:

14048

AN:

84698

European-Finnish (FIN)

AF:

0.262

AC:

13590

AN:

51958

Middle Eastern (MID)

AF:

0.270

AC:

1555

AN:

5764

European-Non Finnish (NFE)

AF:

0.292

AC:

322414

AN:

1105974

Other (OTH)

AF:

0.277

AC:

16653

AN:

60018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

14751

29503

44254

59006

73757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10586

21172

31758

42344

52930

<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:

0.307

AC:

46721

AN:

152010

Hom.:

7851

Cov.:

AF XY:

0.301

AC XY:

22384

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.428

AC:

17731

AN:

41450

American (AMR)

AF:

0.233

AC:

3565

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1197

AN:

3470

East Asian (EAS)

AF:

0.0212

AC:

109

AN:

5144

South Asian (SAS)

AF:

0.153

AC:

740

AN:

4824

European-Finnish (FIN)

AF:

0.256

AC:

2709

AN:

10590

Middle Eastern (MID)

AF:

0.267

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.290

AC:

19685

AN:

67948

Other (OTH)

AF:

0.309

AC:

653

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1593

3187

4780

6374

7967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.303

Hom.:

18671

Bravo

AF:

0.314

Asia WGS

AF:

0.116

AC:

406

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.5

(source)

DANN

Benign

0.66

PhyloP100

-0.39

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