Genetic Variant HOXD9:p.Pro56Arg (chr2-176122935-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014213.4(HOXD9):c.167C>G(p.Pro56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,579,646 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.28

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.167C>G	p.Pro56Arg	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.167C>G	p.Pro56Arg	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-491G>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000981

AC:

AN:

1427380

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

708480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30296

American (AMR)

AF:

0.00

AC:

AN:

40926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25298

East Asian (EAS)

AF:

0.0000551

AC:

AN:

36324

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000911

AC:

AN:

1097466

Other (OTH)

AF:

0.0000170

AC:

AN:

58788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

0.096

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

0.90

PhyloP100

3.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.0

REVEL

Benign

0.28

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.019

Polyphen

0.86

Vest4

0.48

MutPred

0.34

Gain of methylation at P56 (P = 0.0192);

MVP

0.91

MPC

1.3

ClinPred

0.89

GERP RS

3.3

PromoterAI

0.021

Neutral

(source)

Varity_R

0.21

gMVP

0.28

Mutation Taster

=80/20

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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2-176122935-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over