2-176123231-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014213.4(HOXD9):c.463G>T(p.Gly155Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,403,262 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 5 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.48

Publications

2 publications found

Variant links:

Genes affected

HOXD9 (HGNC:5140): (homeobox D9) 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 exact role of this gene has not been determined. [provided by RefSeq, Jul 2008]

HOXD9 links:

HOXD-AS2 (HGNC:43756): (HOXD cluster antisense RNA 2)

HOXD-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017174155).

BP6

Variant 2-176123231-G-T is Benign according to our data. Variant chr2-176123231-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3035685.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 222 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.463G>T	p.Gly155Trp	missense_variant	Exon 1 of 2	ENST00000249499.8	NP_055028.3	P28356

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD9	ENST00000249499.8 link	c.463G>T	p.Gly155Trp	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-787C>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

222

AN:

150062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00222

Gnomad AMR

AF:

0.00100

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.000860

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00204

AC:

163

AN:

79912

AF XY:

0.00195

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.000203

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000656

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00885

GnomAD4 exome

AF:

0.00229

AC:

2870

AN:

1253062

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1374

AN XY:

614100

show subpopulations

African (AFR)

AF:

0.000203

AC:

AN:

24620

American (AMR)

AF:

0.00290

AC:

AN:

23444

Ashkenazi Jewish (ASJ)

AF:

0.000712

AC:

AN:

18252

East Asian (EAS)

AF:

0.00

AC:

AN:

23726

South Asian (SAS)

AF:

0.00145

AC:

AN:

68476

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

41514

Middle Eastern (MID)

AF:

0.000604

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00252

AC:

2522

AN:

998952

Other (OTH)

AF:

0.00189

AC:

AN:

49114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

170

340

511

681

851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00148

AC:

222

AN:

150200

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

102

AN XY:

73410

show subpopulations

African (AFR)

AF:

0.000194

AC:

AN:

41176

American (AMR)

AF:

0.00100

AC:

AN:

15004

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

4814

South Asian (SAS)

AF:

0.00114

AC:

AN:

4370

European-Finnish (FIN)

AF:

0.000860

AC:

AN:

10460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00266

AC:

180

AN:

67612

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00150

ExAC

AF:

0.000864

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HOXD9-related disorder

Benign:1

Feb 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.027

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.61

MVP

0.97

MPC

1.6

ClinPred

0.061

GERP RS

2.6

Varity_R

0.66

gMVP

0.64

Mutation Taster

=92/8

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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2-176123231-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over