chr2-176151907-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014621.3(HOXD4):c.274C>A(p.Pro92Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00052 in 1,594,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

HOXD4
NM_014621.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

Publications

1 publications found

Variant links:

Genes affected

HOXD4 (HGNC:5138): (homeobox D4) 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, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located at 2q31-2q37 chromosome regions. Deletions that removed the entire HOXD gene cluster or 5' end of this cluster have been associated with severe limb and genital abnormalities. The protein encoded by this gene may play a role in determining positional values in developing limb buds. Alternatively spliced variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

HOXD4 links:

HOXD3 (HGNC:5137): (homeobox D3) 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, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located at 2q31-2q37 chromosome regions. Deletions that removed the entire HOXD gene cluster or 5' end of this cluster have been associated with severe limb and genital abnormalities. The protein encoded by this gene may play a role in the regulation of cell adhesion processes. [provided by RefSeq, Jul 2008]

HOXD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060141206).

BS2

High AC in GnomAd4 at 64 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014621.3. 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
	HOXD4	NM_014621.3	MANE Select	c.274C>A	p.Pro92Thr	missense	Exon 1 of 2	NP_055436.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOXD4	ENST00000306324.4	TSL:1 MANE Select	c.274C>A	p.Pro92Thr	missense	Exon 1 of 2	ENSP00000302548.3	P09016
HOXD3	ENST00000963805.1		c.-85+4257C>A		intron	N/A	ENSP00000633864.1
HOXD3	ENST00000432796.2	TSL:3	c.-85+14908C>A		intron	N/A	ENSP00000392615.2	C9J1M3

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000426

AC:

AN:

206478

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000639

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000508

Gnomad FIN exome

AF:

0.000320

Gnomad NFE exome

AF:

0.000588

Gnomad OTH exome

AF:

0.000761

GnomAD4 exome

AF:

0.000530

AC:

765

AN:

1442652

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

384

AN XY:

715942

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

33018

American (AMR)

AF:

0.0000710

AC:

AN:

42230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.000256

AC:

AN:

38988

South Asian (SAS)

AF:

0.000638

AC:

AN:

84690

European-Finnish (FIN)

AF:

0.000454

AC:

AN:

50702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.000578

AC:

637

AN:

1102580

Other (OTH)

AF:

0.000605

AC:

AN:

59498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000420

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41580

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5172

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000430

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.000517

AC:

ExAC

AF:

0.000382

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.079

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.2

PhyloP100

4.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

REVEL

Benign

0.18

Sift

Benign

0.22

Sift4G

Benign

0.14

Polyphen

0.015

Vest4

0.17

MVP

0.93

MPC

0.47

ClinPred

0.033

GERP RS

2.7

PromoterAI

0.030

Neutral

(source)

Varity_R

0.093

gMVP

0.27

Mutation Taster

=289/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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