2-176093058-GGCGGCGGCGGCGGCAGCGGCGGCT-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_000523.4(HOXD13):c.183_206del(p.Ala64_Ala71del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,354,154 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (6 hom.)
• Consequence: HOXD13 NM_000523.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000523.4
• BP6: Variant 2-176093058-GGCGGCGGCGGCGGCAGCGGCGGCT-G is Benign according to our data. Variant chr2-176093058-GGCGGCGGCGGCGGCAGCGGCGGCT-G is described in ClinVar as [Likely_benign]. Clinvar id is 2651558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD13	NM_000523.4	c.183_206del	p.Ala64_Ala71del	inframe_deletion	1/2	ENST00000392539.4
HOXD13	XM_011511068.3	c.725-1407_725-1384del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4	c.183_206del	p.Ala64_Ala71del	inframe_deletion	1/2	1	NM_000523.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000929 AC: 14 AN: 150728 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000743

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000729 AC: 14 AN: 19196 Hom.: 4 AF XY: 0.000417 AC XY: 5 AN XY: 11994

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000544

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000914 AC: 110 AN: 1203426 Hom.: 6 AF XY: 0.0000801 AC XY: 47 AN XY: 586650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000914

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.0000929 AC: 14 AN: 150728 Hom.: 0 Cov.: 33 AF XY: 0.0000816 AC XY: 6 AN XY: 73550

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000462

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000743

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

HOXD13-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

HOXD13: BS2 -

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: rs756844068; hg19: chr2-176957786;