rs878854343

Variant names:

• chr2-176093212-CCAGCACCCACGCCT-C
• rs878854343
• NM_000523.4:c.323_336delCAGCACCCACGCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000523.4(HOXD13):​c.323_336delCAGCACCCACGCCT​(p.Pro108ArgfsTer124) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXD13 NM_000523.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.24
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-176093212-CCAGCACCCACGCCT-C is Pathogenic according to our data. Variant chr2-176093212-CCAGCACCCACGCCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 14867.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4	c.323_336delCAGCACCCACGCCT	p.Pro108ArgfsTer124	frameshift_variant	Exon 1 of 2	ENST00000392539.4	NP_000514.2
HOXD13	XM_011511068.3	c.725-1267_725-1254delCAGCACCCACGCCT		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	c.323_336delCAGCACCCACGCCT	p.Pro108ArgfsTer124	frameshift_variant	Exon 1 of 2	1	NM_000523.4	ENSP00000376322.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Synpolydactyly type 1 Pathogenic:1

Oct 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=51/149	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs878854343; hg19: chr2-176957940;