Variant chr2-176122788-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014213.4(HOXD9):c.20G>A(p.Gly7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,525,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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:):

HOXD-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017316848).

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD9	NM_014213.4 linkuse as main transcript	c.20G>A	p.Gly7Glu	missense_variant	1/2	ENST00000249499.8	NP_055028.3	P28356

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD9	ENST00000249499.8 linkuse as main transcript	c.20G>A	p.Gly7Glu	missense_variant	1/2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 linkuse as main transcript	n.498-344C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000289

AC:

AN:

173004

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

93844

show subpopulations

Gnomad AFR exome

AF:

0.000270

Gnomad AMR exome

AF:

0.000195

Gnomad ASJ exome

AF:

0.00350

Gnomad EAS exome

AF:

0.000419

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000523

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.000210

AC:

288

AN:

1373166

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

152

AN XY:

678708

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000132

Gnomad4 ASJ exome

AF:

0.00389

Gnomad4 EAS exome

AF:

0.000286

Gnomad4 SAS exome

AF:

0.0000826

Gnomad4 FIN exome

AF:

0.0000774

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.000230

GnomAD4 genome

AF:

0.000276

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000558

Hom.:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.20G>A (p.G7E) alteration is located in exon 1 (coding exon 1) of the HOXD9 gene. This alteration results from a G to A substitution at nucleotide position 20, causing the glycine (G) at amino acid position 7 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.039

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.59

REVEL

Benign

0.18

Sift

Benign

0.21

Sift4G

Benign

0.32

Polyphen

0.10

Vest4

0.15

MutPred

0.17

Loss of MoRF binding (P = 0.0262);

MVP

0.86

MPC

0.69

ClinPred

0.0070

GERP RS

3.4

Varity_R

0.13

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over