rs536639583

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000523.4(HOXD13):c.32G>C(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,329,670 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

HOXD13
NM_000523.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: 0.282

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

brachydactyly-syndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
synpolydactyly type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
brachydactyly type E
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 5
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HOXD13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.118177116).

BP6

Variant 2-176092922-G-C is Benign according to our data. Variant chr2-176092922-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225651.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000856 (130/151790) while in subpopulation EAS AF = 0.022 (113/5136). AF 95% confidence interval is 0.0187. There are 1 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4 link	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 2	ENST00000392539.4	NP_000514.2	P35453
HOXD13	XM_011511068.3 link	c.725-1558G>C		intron_variant	Intron 1 of 1		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4 link	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 2	1	NM_000523.4	ENSP00000376322.3		P35453

Frequencies

GnomAD3 genomes

AF:

0.000857

AC:

130

AN:

151682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0219

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000185

AC:

AN:

37778

AF XY:

0.000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00400

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000454

AC:

535

AN:

1177880

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

252

AN XY:

575020

show subpopulations

African (AFR)

AF:

0.0000429

AC:

AN:

23296

American (AMR)

AF:

0.00

AC:

AN:

13218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17532

East Asian (EAS)

AF:

0.0167

AC:

428

AN:

25650

South Asian (SAS)

AF:

0.000693

AC:

AN:

46166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3380

European-Non Finnish (NFE)

AF:

0.00000923

AC:

AN:

975526

Other (OTH)

AF:

0.00138

AC:

AN:

47072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000856

AC:

130

AN:

151790

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41516

American (AMR)

AF:

0.000263

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0220

AC:

113

AN:

5136

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67890

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.00106

ExAC

AF:

0.000528

AC:

Asia WGS

AF:

0.00499

AC:

AN:

3418

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Mar 15, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The G11A variant has been published previously in association with a synpolydactyly phenotype; the homozygous proband was more severely affected than the heterozygous mother, but the father's phenotype was not provided (Brison et al., 2012). However, the variant has also been observed in the homozygous state at GeneDx in an individual whose phenotype did not match a HOXD13 presentation. The variant is observed in 3/1714 (0.175%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). G11A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Functional studies have shown that G11A has no effect on DNA binding, transactivation, or localization; however, it speeds protein degradation and led to skeletal abnormalities in chick embryos (Brison et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HOXD13: PP3, BS1 -

Synpolydactyly type 1

Pathogenic:1

Jul 20, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Brachydactyly type D;C1862102:Brachydactyly type E1

Uncertain:1

Oct 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.69

PhyloP100

0.28

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.88

REVEL

Uncertain

0.62

Sift

Benign

0.12

Sift4G

Benign

0.17

Polyphen

0.95

Vest4

0.71

MutPred

0.66

Gain of helix (P = 0.0034);

MVP

0.95

ClinPred

0.16

GERP RS

2.3

PromoterAI

0.046

Neutral

(source)

Varity_R

0.13

gMVP

0.39

Mutation Taster

=93/7

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs536639583

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over