rs3832095

chr2-176093057-GGGCGGCGGCGGC-Gchr2-176093057-GGGCGGCGGCGGC-GGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCchr2-176093057-GGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_000523.4(HOXD13):c.171_182del(p.Ala68_Ala71del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,369,924 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (9 hom.)
• Consequence: HOXD13 NM_000523.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 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 eas. gnomad4 allele frequency = 0.000205 (31/150896) while in subpopulation EAS AF= 0.00508 (26/5114). AF 95% confidence interval is 0.00356. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD13	NM_000523.4	c.171_182del	p.Ala68_Ala71del	inframe_deletion	1/2	ENST00000392539.4
HOXD13	XM_011511068.3	c.725-1419_725-1408del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD13	ENST00000392539.4	c.171_182del	p.Ala68_Ala71del	inframe_deletion	1/2	1	NM_000523.4	P1

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 31 AN: 150788 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00507

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.00158 AC: 34 AN: 21526 Hom.: 5 AF XY: 0.00126 AC XY: 17 AN XY: 13458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0327

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.000152 AC: 185 AN: 1219028 Hom.: 9 AF XY: 0.000139 AC XY: 83 AN XY: 595810

Gnomad4 AFR exome AF: 0.0000833

Gnomad4 AMR exome AF: 0.000189

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.96e-7

Gnomad4 OTH exome AF: 0.000460

GnomAD4 genome AF: 0.000205 AC: 31 AN: 150896 Hom.: 0 Cov.: 33 AF XY: 0.000217 AC XY: 16 AN XY: 73668

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00508

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000480

Bravo AF: 0.000159

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 09, 2023

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. This variant is also known as c.171_182delGGCGGCGGCGGC p.56_60delAAAA. This variant has been observed in individual(s) with clinical features of synpolydactyly and/or polydactyly (PMID: 18399101, 33533119). It has also been observed to segregate with disease in related individuals. 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.171_182del, results in the deletion of 4 amino acid(s) of the HOXD13 protein (p.Ala68_Ala71del), but otherwise preserves the integrity of the reading frame. -

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: rs3832095; hg19: chr2-176957785;