Genetic Variant NM_014213.4:c.590G>A (chr2-176123358-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014213.4(HOXD9):c.590G>A(p.Arg197Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,550,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11334312).

BS2

High AC in GnomAdExome4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.590G>A	p.Arg197Gln	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.590G>A	p.Arg197Gln	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-914C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000275

AC:

AN:

145324

AF XY:

0.0000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000937

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000377

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000436

AC:

AN:

1397852

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

689528

show subpopulations

African (AFR)

AF:

0.0000318

AC:

AN:

31494

American (AMR)

AF:

0.0000841

AC:

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35618

South Asian (SAS)

AF:

0.00

AC:

AN:

79092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000528

AC:

AN:

1078768

Other (OTH)

AF:

0.00

AC:

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000190

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.590G>A (p.R197Q) 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 590, causing the arginine (R) at amino acid position 197 to be replaced by a glutamine (Q). 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

0.098

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.11

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.4

PhyloP100

1.4

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.29

Sift4G

Benign

0.26

Polyphen

0.97

Vest4

0.28

MVP

0.91

MPC

0.62

ClinPred

0.12

GERP RS

4.1

Varity_R

0.21

gMVP

0.44

Mutation Taster

=98/2

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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NM_014213.4:c.590G>A

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