2-176094645-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000523.4(HOXD13):c.947C>G(p.Ser316Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.08

Publications

6 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000523.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 2-176094645-C-G is Pathogenic according to our data. Variant chr2-176094645-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14870.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4 link	c.947C>G	p.Ser316Cys	missense_variant	Exon 2 of 2	ENST00000392539.4	NP_000514.2	P35453
HOXD13	XM_011511068.3 link	c.890C>G	p.Ser297Cys	missense_variant	Exon 2 of 2		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4 link	c.947C>G	p.Ser316Cys	missense_variant	Exon 2 of 2	1	NM_000523.4	ENSP00000376322.3		P35453

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111810

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brachydactyly type E

Pathogenic:1

Apr 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

May 06, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.947C>G (p.S316C) alteration is located in exon 2 (coding exon 2) of the HOXD13 gene. This alteration results from a C to G substitution at nucleotide position 947, causing the serine (S) at amino acid position 316 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant, reported as c.923C>G (p.S308C), has been detected segregating with disease in a family with various distal limb skeletal abnormalities (Johnson, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Brachydactyly type D

Pathogenic:1

Apr 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Aug 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro functional analysis does not indicate that p.(S316C) alters HOXD13 ability to bind DNA (PMID: 27013732, 12649808); Reported as c.923C>G; p.(S308C) in a family with limb malformations; however, specific familial segregation information was not provided (PMID: 12649808); This variant is associated with the following publications: (PMID: 24789103, 27013732, 12649808) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

PhyloP100

6.1

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.85

Loss of disorder (P = 0.0179);

MVP

0.98

ClinPred

1.0

GERP RS

4.8

Varity_R

0.88

gMVP

0.74

Mutation Taster

=34/66

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over