2-176092896-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000523.4(HOXD13):​c.6C>A​(p.Ser2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,276,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780
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 Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36838415).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HOXD13NM_000523.4 linkuse as main transcriptc.6C>A p.Ser2Arg missense_variant 1/2 ENST00000392539.4 NP_000514.2
HOXD13XM_011511068.3 linkuse as main transcriptc.725-1584C>A intron_variant XP_011509370.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HOXD13ENST00000392539.4 linkuse as main transcriptc.6C>A p.Ser2Arg missense_variant 1/21 NM_000523.4 ENSP00000376322 P1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
151746
Hom.:
0
Cov.:
33
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00955
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.000479
GnomAD4 exome
AF:
0.0000702
AC:
79
AN:
1124566
Hom.:
0
Cov.:
30
AF XY:
0.0000590
AC XY:
32
AN XY:
542794
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:
0.0000812
Gnomad4 OTH exome
AF:
0.0000223
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
151852
Hom.:
0
Cov.:
33
AF XY:
0.0000674
AC XY:
5
AN XY:
74216
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000302

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), LabcorpJun 23, 2023An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In 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. This variant has not been reported in the literature in individuals affected with HOXD13-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2 of the HOXD13 protein (p.Ser2Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Uncertain
0.069
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.42
T
M_CAP
Pathogenic
0.85
D
MetaRNN
Benign
0.37
T
MetaSVM
Uncertain
0.16
D
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
0.65
D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-0.37
N
REVEL
Uncertain
0.33
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.021
D
Polyphen
0.013
B
Vest4
0.19
MutPred
0.11
Loss of phosphorylation at S2 (P = 0.0074);
MVP
0.94
ClinPred
0.47
T
GERP RS
2.1
Varity_R
0.23
gMVP
0.38

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: rs1353221462; hg19: chr2-176957624; API