2-176122788-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014213.4(HOXD9):c.20G>C(p.Gly7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,525,404 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 27 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 26 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.36

Publications

4 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004009187).

BP6

Variant 2-176122788-G-C is Benign according to our data. Variant chr2-176122788-G-C is described in ClinVar as [Benign]. Clinvar id is 775791.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1366/152240) while in subpopulation AFR AF = 0.0318 (1321/41558). AF 95% confidence interval is 0.0304. There are 27 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.20G>C	p.Gly7Ala	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.20G>C	p.Gly7Ala	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-344C>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00895

AC:

1362

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00213

AC:

369

AN:

173004

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000470

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.000862

AC:

1184

AN:

1373164

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

537

AN XY:

678708

show subpopulations

African (AFR)

AF:

0.0346

AC:

960

AN:

27730

American (AMR)

AF:

0.00208

AC:

AN:

30222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20796

East Asian (EAS)

AF:

0.0000572

AC:

AN:

34938

South Asian (SAS)

AF:

0.000124

AC:

AN:

72602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51704

Middle Eastern (MID)

AF:

0.00111

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.0000391

AC:

AN:

1073366

Other (OTH)

AF:

0.00181

AC:

102

AN:

56404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00897

AC:

1366

AN:

152240

Hom.:

Cov.:

AF XY:

0.00852

AC XY:

634

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0318

AC:

1321

AN:

41558

American (AMR)

AF:

0.00176

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68006

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000558

Hom.:

Bravo

AF:

0.0105

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00277

AC:

335

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.039

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.48

MutationAssessor

Benign

-0.34

PhyloP100

2.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.60

REVEL

Benign

0.22

Sift

Benign

0.18

Sift4G

Benign

0.26

Polyphen

0.0090

Vest4

0.15

MVP

0.86

MPC

0.58

ClinPred

0.0031

GERP RS

3.4

PromoterAI

-0.13

Neutral

(source)

Varity_R

0.12

gMVP

0.16

Mutation Taster

=96/4

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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2-176122788-G-C

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