2-176100176-G-A

Variant names:

• chr2-176100176-G-A
• rs847151
• NM_021193.4:c.375G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_021193.4(HOXD12):​c.375G>A​(p.Leu125Leu) 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
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021193.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD12	NM_021193.4	MANE Select	c.375G>A	p.Leu125Leu	synonymous	Exon 1 of 2	NP_067016.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD12	ENST00000406506.4	TSL:3 MANE Select	c.375G>A	p.Leu125Leu	synonymous	Exon 1 of 2	ENSP00000385586.2
	HOXD12	ENST00000404162.2	TSL:1	c.375G>A	p.Leu125Leu	synonymous	Exon 1 of 2	ENSP00000385132.2

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

GnomAD2 exomes AF: 0.314 AC: 75844 AN: 241292 AF XY: 0.305

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 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

African (AFR) AF: 0.482 AC: 16117 AN: 33464

American (AMR) AF: 0.437 AC: 19490 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7174 AN: 26096

East Asian (EAS) AF: 0.0473 AC: 1876 AN: 39688

South Asian (SAS) AF: 0.235 AC: 20294 AN: 86206

European-Finnish (FIN) AF: 0.290 AC: 15073 AN: 51974

Middle Eastern (MID) AF: 0.298 AC: 1719 AN: 5760

European-Non Finnish (NFE) AF: 0.338 AC: 376086 AN: 1111600

Other (OTH) AF: 0.322 AC: 19421 AN: 60324

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

African (AFR) AF: 0.473 AC: 19645 AN: 41540

American (AMR) AF: 0.375 AC: 5734 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 997 AN: 3470

East Asian (EAS) AF: 0.0637 AC: 329 AN: 5168

South Asian (SAS) AF: 0.225 AC: 1088 AN: 4828

European-Finnish (FIN) AF: 0.296 AC: 3136 AN: 10604

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22477 AN: 67996

Other (OTH) AF: 0.338 AC: 713 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		3.3
PromoterAI		-0.018	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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