rs847151

chr2-176100176-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_021193.4(HOXD12):c.375G>A(p.Leu125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,611,982 control chromosomes in the GnomAD database, including 91,941 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 0.36 (10378 hom., cov: 34)
  • Exomes 𝑓: 0.33 (81563 hom.)
• Consequence: HOXD12 NM_021193.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33

Genes affected

HOXD12 (HGNC:5135): (homeobox D12) 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 exact role of this gene has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD12	NM_021193.4	c.375G>A	p.Leu125=	synonymous_variant	1/2	ENST00000406506.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD12	ENST00000406506.4	c.375G>A	p.Leu125=	synonymous_variant	1/2	3	NM_021193.4	P1
HOXD12	ENST00000404162.2	c.375G>A	p.Leu125=	synonymous_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54197 AN: 152108 Hom.: 10360 Cov.: 34

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.337

GnomAD3 exomes AF: 0.314 AC: 75844 AN: 241292 Hom.: 13232 AF XY: 0.305 AC XY: 40356 AN XY: 132210

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.0636

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.327 AC: 477250 AN: 1459756 Hom.: 81563 Cov.: 42 AF XY: 0.323 AC XY: 234594 AN XY: 726148

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.0473

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.356 AC: 54253 AN: 152226 Hom.: 10378 Cov.: 34 AF XY: 0.350 AC XY: 26020 AN XY: 74440

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.0637

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.338

Alfa AF: 0.338 Hom.: 3830

Bravo AF: 0.369

Asia WGS AF: 0.193 AC: 675 AN: 3478

EpiCase AF: 0.326

EpiControl AF: 0.322

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	10
Dann	Benign	0.90

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: rs847151; hg19: chr2-176964904; COSMIC: COSV66832403; COSMIC: COSV66832403;