rs878854345

Positions:

• chr2-176093094-G-GGCGGCGGCTGCGGCGGCGGCA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_000523.4(HOXD13):​c.209_210insGGCTGCGGCGGCGGCAGCGGC​(p.Ala65_Ala71dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A68A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXD13 NM_000523.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.98

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-176093094-G-GGCGGCGGCTGCGGCGGCGGCA is Pathogenic according to our data. Variant chr2-176093094-G-GGCGGCGGCTGCGGCGGCGGCA is described in ClinVar as [Pathogenic]. Clinvar id is 14873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_000523.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD13	NM_000523.4	c.209_210insGGCTGCGGCGGCGGCAGCGGC	p.Ala65_Ala71dup	inframe_insertion	1/2	ENST00000392539.4	NP_000514.2
HOXD13	XM_011511068.3	c.725-1381_725-1380insGGCTGCGGCGGCGGCAGCGGC		intron_variant			XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4	c.209_210insGGCTGCGGCGGCGGCAGCGGC	p.Ala65_Ala71dup	inframe_insertion	1/2	1	NM_000523.4	ENSP00000376322	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndactyly type 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2023	- -

Synpolydactyly type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute for Genomic Medicine, Nationwide Children's Hospital

Mar 25, 2021

The c.209_210insGGCTGCGGCGGCGGCAGCGGC variant is predicted to cause a 7-residue expansion of the polyalanine tract in exon 1 of HOXD13. This variant was first reported to cause dominant synpolydactyly more than 20 years ago and has been described in multiple unrelated synpolydactyly kindreds (PMID: 9207113). In our research study, we sequenced three members of a family with four documented generations of polysyndactyly. After identifying a similar variant (9-alanine dup) in a different family with this condition, we observed suggestive evidence of a similar event in this trio, and performed Sanger sequencing to confirm the 21-bp duplication in the proband and affected father. The variant is absent from population frequency databases (gnomAD). Functional studies of the polyalanine repeat in exon 1 have shown that an increase of the Ala repeat above a certain length (22 Ala) is associated with a shift in the localization of Hoxd13 from nuclear to cytoplasmic, where it forms large amorphous aggregates (PMID: 15333588). We interpret the variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854345; hg19: chr2-176957822;