rs191379716

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_014213.4(HOXD9):c.463G>C(p.Gly155Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,403,266 control chromosomes in the GnomAD database, including 1 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. G155W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 1 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=0.029539794).

BP6

Variant 2-176123231-G-C is Benign according to our data. Variant chr2-176123231-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3043845.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.463G>C	p.Gly155Arg	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>C	p.Gly155Arg	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-787C>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.000586

AC:

AN:

150062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000731

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000916

Gnomad FIN

AF:

0.000669

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000826

AC:

AN:

79912

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000719

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.000466

GnomAD4 exome

AF:

0.000871

AC:

1091

AN:

1253066

Hom.:

Cov.:

AF XY:

0.000962

AC XY:

591

AN XY:

614098

show subpopulations

African (AFR)

AF:

0.0000812

AC:

AN:

24620

American (AMR)

AF:

0.0000427

AC:

AN:

23446

Ashkenazi Jewish (ASJ)

AF:

0.0000548

AC:

AN:

18252

East Asian (EAS)

AF:

0.00

AC:

AN:

23726

South Asian (SAS)

AF:

0.00177

AC:

121

AN:

68474

European-Finnish (FIN)

AF:

0.00128

AC:

AN:

41514

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.000879

AC:

878

AN:

998954

Other (OTH)

AF:

0.000590

AC:

AN:

49116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000586

AC:

AN:

150200

Hom.:

Cov.:

AF XY:

0.000613

AC XY:

AN XY:

73410

show subpopulations

African (AFR)

AF:

0.0000729

AC:

AN:

41176

American (AMR)

AF:

0.000200

AC:

AN:

15004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

4814

South Asian (SAS)

AF:

0.000915

AC:

AN:

4370

European-Finnish (FIN)

AF:

0.000669

AC:

AN:

10460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

67612

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000219

Hom.:

Bravo

AF:

0.000453

ExAC

AF:

0.000236

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HOXD9-related disorder

Benign:1

Mar 20, 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

0.50

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.030

MetaSVM

Uncertain

-0.00030

MutationAssessor

Benign

1.9

PhyloP100

3.5

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.46

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.96

Vest4

0.37

MutPred

0.55

Gain of methylation at G155 (P = 0.0216);

MVP

0.97

MPC

1.2

ClinPred

0.33

GERP RS

2.6

Varity_R

0.52

gMVP

0.64

Mutation Taster

=89/11

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

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rs191379716

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