Variant 2-176117056-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002148.4(HOXD10):c.223A>G(p.Ile75Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,878 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 1 hom. )

Consequence

HOXD10
NM_002148.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Variant links:

Genes affected

HOXD10 (HGNC:5133): (homeobox D10) This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox D genes located on chromosome 2. The encoded nuclear protein functions as a sequence-specific transcription factor that is expressed in the developing limb buds and is involved in differentiation and limb development. Mutations in this gene have been associated with Wilm's tumor and congenital vertical talus (also known as "rocker-bottom foot" deformity or congenital convex pes valgus) and/or a foot deformity resembling that seen in Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]

HOXD10 links:

HOXD10 (HGNC:):

HOXD10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21428338).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD10	NM_002148.4 linkuse as main transcript	c.223A>G	p.Ile75Val	missense_variant	1/2	ENST00000249501.5	NP_002139.2	P28358

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HOXD10	ENST00000249501.5 linkuse as main transcript	c.223A>G	p.Ile75Val	missense_variant	1/2	1	NM_002148.4	ENSP00000249501.4	P28358
HOXD10	ENST00000490088.2 linkuse as main transcript	n.570-1898A>G		intron_variant		2
HOXD10	ENST00000549469.1 linkuse as main transcript	n.617-1898A>G		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251458

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.223A>G (p.I75V) alteration is located in exon 1 (coding exon 1) of the HOXD10 gene. This alteration results from a A to G substitution at nucleotide position 223, causing the isoleucine (I) at amino acid position 75 to be replaced by a valine (V). 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

0.14

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

0.0049

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

M_CAP

Benign

0.0073

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.59

REVEL

Benign

0.078

Sift

Benign

0.22

Sift4G

Benign

0.39

Polyphen

0.021

Vest4

0.28

MutPred

0.30

Gain of disorder (P = 0.0933);

MVP

0.66

MPC

0.35

ClinPred

0.41

GERP RS

5.8

Varity_R

0.17

gMVP

0.23

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