chr2-176093054-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000523.4(HOXD13):ā€‹c.164G>Cā€‹(p.Gly55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000818 in 1,223,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 8.2e-7 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68
Variant links:
Genes affected
HOXD13 (HGNC:5136): (homeobox D13) 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 in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31749454).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HOXD13NM_000523.4 linkuse as main transcriptc.164G>C p.Gly55Ala missense_variant 1/2 ENST00000392539.4 NP_000514.2
HOXD13XM_011511068.3 linkuse as main transcriptc.725-1426G>C intron_variant XP_011509370.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HOXD13ENST00000392539.4 linkuse as main transcriptc.164G>C p.Gly55Ala missense_variant 1/21 NM_000523.4 ENSP00000376322 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
8.18e-7
AC:
1
AN:
1223048
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
597788
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:
0.0000327
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with HOXD13-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 55 of the HOXD13 protein (p.Gly55Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
23
DANN
Benign
0.95
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.72
T
M_CAP
Pathogenic
0.92
D
MetaRNN
Benign
0.32
T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-0.61
N
REVEL
Benign
0.23
Sift
Benign
0.21
T
Sift4G
Benign
0.47
T
Polyphen
0.025
B
Vest4
0.20
MutPred
0.30
Gain of helix (P = 0.0078);
MVP
0.90
ClinPred
0.094
T
GERP RS
3.4
Varity_R
0.095
gMVP
0.41

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.

Other links and lift over

dbSNP: rs1443225761; hg19: chr2-176957782; API