2-176109394-G-A

Position:

• chr2-176109394-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021192.3(HOXD11):​c.*252G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 445,660 control chromosomes in the GnomAD database, including 11,590 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4852 hom., cov: 33)
  • Exomes 𝑓: 0.21 (6738 hom.)
• Consequence: HOXD11 NM_021192.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535

Genes affected

HOXD11 (HGNC:5134): (homeobox D11) 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. The product of the mouse Hoxd11 gene plays a role in forelimb morphogenesis. [provided by RefSeq, Jul 2008]

HOXD10 (HGNC:5133): (homeobox D10) This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox D genes located on chromosome 2. The encoded nuclear protein functions as a sequence-specific transcription factor that is expressed in the developing limb buds and is involved in differentiation and limb development. Mutations in this gene have been associated with Wilm's tumor and congenital vertical talus (also known as "rocker-bottom foot" deformity or congenital convex pes valgus) and/or a foot deformity resembling that seen in Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD11	NM_021192.3	c.*252G>A		3_prime_UTR_variant	2/2	ENST00000249504.7	NP_067015.2
HOXD11	XR_007073114.1	n.1309+36G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD11	ENST00000249504.7	c.*252G>A		3_prime_UTR_variant	2/2	3	NM_021192.3	ENSP00000249504	P1
HOXD11	ENST00000498438.1	n.899G>A		non_coding_transcript_exon_variant	2/2	1
HOXD10	ENST00000490088.2	n.569+36G>A		intron_variant, non_coding_transcript_variant		2
HOXD10	ENST00000549469.1	n.482+36G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37394 AN: 152042 Hom.: 4832 Cov.: 33

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.210 AC: 61657 AN: 293500 Hom.: 6738 Cov.: 0 AF XY: 0.209 AC XY: 31554 AN XY: 151090

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.246 AC: 37454 AN: 152160 Hom.: 4852 Cov.: 33 AF XY: 0.243 AC XY: 18102 AN XY: 74394

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.209

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.222

Alfa AF: 0.222 Hom.: 3720

Bravo AF: 0.247

Asia WGS AF: 0.213 AC: 741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.2
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs6745764; hg19: chr2-176974122;