chr2-176151875-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014621.3(HOXD4):c.242A>T(p.Glu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,585,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

HOXD4
NM_014621.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.80

Publications

10 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21931592).

BS2

High AC in GnomAd4 at 130 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.242A>T	p.Glu81Val	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.242A>T	p.Glu81Val	missense	Exon 1 of 2	ENSP00000302548.3	P09016
HOXD3	ENST00000963805.1		c.-85+4225A>T		intron	N/A	ENSP00000633864.1
HOXD3	ENST00000432796.2	TSL:3	c.-85+14876A>T		intron	N/A	ENSP00000392615.2	C9J1M3

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

130

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000791

AC:

152

AN:

192114

AF XY:

0.000710

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.000443

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00128

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.00149

AC:

2131

AN:

1433096

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

999

AN XY:

710238

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32800

American (AMR)

AF:

0.000493

AC:

AN:

40548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25596

East Asian (EAS)

AF:

0.00

AC:

AN:

38380

South Asian (SAS)

AF:

0.00

AC:

AN:

83976

European-Finnish (FIN)

AF:

0.000742

AC:

AN:

49892

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.00181

AC:

1989

AN:

1097508

Other (OTH)

AF:

0.00139

AC:

AN:

59136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

122

245

367

490

612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<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:

0.000854

AC:

130

AN:

152198

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41560

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00163

AC:

111

AN:

67978

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00100

Hom.:

Bravo

AF:

0.000774

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.000583

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukemia, acute lymphoblastic, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.15

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.5

PhyloP100

6.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.46

Sift

Benign

0.24

Sift4G

Benign

0.26

Polyphen

0.11

Vest4

0.80

MVP

0.87

MPC

0.50

ClinPred

0.058

GERP RS

3.1

PromoterAI

-0.096

Neutral

(source)

Varity_R

0.15

gMVP

0.41

Mutation Taster

=64/36

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