Genetic Variant HOXD9:p.Cys66Arg (chr2-176122964-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014213.4(HOXD9):c.196T>C(p.Cys66Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HOXD9
NM_014213.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.39

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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4 link	c.196T>C	p.Cys66Arg	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.196T>C	p.Cys66Arg	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6		P28356
HOXD-AS2	ENST00000440016.6 link	n.498-520A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30748

American (AMR)

AF:

0.00

AC:

AN:

42992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25516

East Asian (EAS)

AF:

0.00

AC:

AN:

37588

South Asian (SAS)

AF:

0.00

AC:

AN:

84170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1104000

Other (OTH)

AF:

0.00

AC:

AN:

59304

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.196T>C (p.C66R) alteration is located in exon 1 (coding exon 1) of the HOXD9 gene. This alteration results from a T to C substitution at nucleotide position 196, causing the cysteine (C) at amino acid position 66 to be replaced by an arginine (R). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

2.9

PhyloP100

7.4

PrimateAI

Pathogenic

0.98

PROVEAN

Pathogenic

-9.4

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.91

Gain of MoRF binding (P = 0.0134);

MVP

0.97

MPC

2.0

ClinPred

1.0

GERP RS

3.9

PromoterAI

0.15

Neutral

(source)

Varity_R

0.98

gMVP

0.73

Mutation Taster

=6/94

disease causing

(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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2-176122964-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over