rs200750564

Positions:

chr2-176094518-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000523.4(HOXD13):c.820C>T(p.Arg274*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,792 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PP5

Variant 2-176094518-C-T is Pathogenic according to our data. Variant chr2-176094518-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-176094518-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD13	NM_000523.4 linkuse as main transcript	c.820C>T	p.Arg274*	stop_gained	2/2	ENST00000392539.4	NP_000514.2	P35453
HOXD13	XM_011511068.3 linkuse as main transcript	c.763C>T	p.Arg255*	stop_gained	2/2		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4 linkuse as main transcript	c.820C>T	p.Arg274*	stop_gained	2/2	1	NM_000523.4	ENSP00000376322.3		P35453

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152024

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251468

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727194

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HOXD13: PVS1:Strong, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Has been reported previously in association with brachydactyly, in an affected individual and her affected father (PMID: 22233338); Has been reported as heterzygous in a fetus with mesoaxial hand polydactyly as well as other congential anomalies (Sabau et al., 2023) [Sabau DI et al. https://doi.org/10.20944/preprints202309.1240.v1]; has also been reported in the homozygous state in a fetus with bilateral syndactyly and oligodactyly; parents were reported as heterozygous but their clinical details were not specific in this report (PMID: 35574990); Nonsense variant predicted to result in protein truncation, as the last 70 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26046366, 35574990, 22233338, Sabau2023[Article]) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2020

The c.820C>T (p.R274*) alteration, located in exon 2 (coding exon 2) of the HOXD13 gene, consists of a C to T substitution at nucleotide position 820. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 274. This alteration occurs at the 3' terminus of the HOXD13 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 70 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the HOXD13 c.820C>T alteration was observed in <0.01% (2/251468) of total alleles studied. This alteration was previously identified in the heterozygous state in a 28 year old female proband of Polish descent and her father with isolated brachydactyly type E. The proband had shortening of the Vth right metacarpal without shortening of IVth metacarpals, bilateral shortening and broadening of the 1st metacarpals, bilateral shortened, trapezoid middle phalanges of Vth fingers resulting in severe clinodactyly, as well as contractures and deviations of the II-IV fingers and normal feet. The proband's father presented with finger contractures, shortening of the Vth fingers and toes most probably due to shortened Vth metacarpals and metatarsal, shortened finger nails of the Vth fingers most likely resulting from hypoplastic distal phalanges, and short thumbs (Jamsheer, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

Synpolydactyly type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. This variant was detected in homozygous state. -

Male infertility;C0028960:Oligospermia;C0039075:Syndactyly;C0152427:Polydactyly;C1691215:Penile hypospadias;C4021606:Mesoaxial hand polydactyly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 04, 2015

- -

Brachydactyly-syndactyly syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 28, 2017

- -

Brachydactyly type D;C1853137:Brachydactyly-syndactyly syndrome;C1861348:Syndactyly type 5;C1862102:Brachydactyly type E1;C5574994:Synpolydactyly type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 27, 2022

- -

Synpolydactyly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pars Genome Lab

We found this variant in a family with multiple affected siblings in homozygous state. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

Vest4

0.97

GERP RS

4.0

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