Variant 2-176092896-C-A details in Genebe, Genetics Data Aggregator

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

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]

HOXD13 links:

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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	UniProt
HOXD13	NM_000523.4 linkuse as main transcript	c.6C>A	p.Ser2Arg	missense_variant	1/2	ENST00000392539.4
HOXD13	XM_011511068.3 linkuse as main transcript	c.725-1584C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4 linkuse as main transcript	c.6C>A	p.Ser2Arg	missense_variant	1/2	1	NM_000523.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151746

Hom.:

Cov.:

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:

AN:

1124566

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

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:

AN:

151852

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

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.:

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 submitter

clinical testing

Invitae

Jun 23, 2023

An 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

BayesDel_noAF

Benign

-0.14

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.65

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

Polyphen

0.013

Vest4

0.19

MutPred

0.11

Loss of phosphorylation at S2 (P = 0.0074);

MVP

0.94

ClinPred

0.47

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.

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