2-176093057-GGGCGGCGGCGGCGGCAGCGGCGGCTGC-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2
The NM_000523.4(HOXD13):βc.186_212delβ(p.Ala63_Ala71del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,369,900 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.00017 ( 0 hom., cov: 33)
Exomes π: 0.00017 ( 13 hom. )
Consequence
HOXD13
NM_000523.4 inframe_deletion
NM_000523.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.39
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_000523.4
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000166 (25/150892) while in subpopulation SAS AF= 0.00146 (7/4796). AF 95% confidence interval is 0.000685. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 13 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HOXD13 | NM_000523.4 | c.186_212del | p.Ala63_Ala71del | inframe_deletion | 1/2 | ENST00000392539.4 | NP_000514.2 | |
HOXD13 | XM_011511068.3 | c.725-1404_725-1378del | intron_variant | XP_011509370.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HOXD13 | ENST00000392539.4 | c.186_212del | p.Ala63_Ala71del | inframe_deletion | 1/2 | 1 | NM_000523.4 | ENSP00000376322 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000166 AC: 25AN: 150784Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00172 AC: 37AN: 21526Hom.: 8 AF XY: 0.00186 AC XY: 25AN XY: 13458
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GnomAD4 exome AF: 0.000170 AC: 207AN: 1219008Hom.: 13 AF XY: 0.000195 AC XY: 116AN XY: 595802
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GnomAD4 genome AF: 0.000166 AC: 25AN: 150892Hom.: 0 Cov.: 33 AF XY: 0.000217 AC XY: 16AN XY: 73666
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2022 | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.186_212del, results in the deletion of 9 amino acid(s) of the HOXD13 protein (p.Ala63_Ala71del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with HOXD13-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at