2-176100358-G-T

Variant names:

• chr2-176100358-G-T
• NM_021193.4:c.557G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021193.4(HOXD12):​c.557G>T​(p.Arg186Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HOXD12 NM_021193.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD12	NM_021193.4	c.557G>T	p.Arg186Leu	missense_variant	Exon 1 of 2	ENST00000406506.4	NP_067016.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD12	ENST00000406506.4	c.557G>T	p.Arg186Leu	missense_variant	Exon 1 of 2	3	NM_021193.4	ENSP00000385586.2
HOXD12	ENST00000404162.2	c.557G>T	p.Arg186Leu	missense_variant	Exon 1 of 2	1		ENSP00000385132.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459986 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.94	P;D
Vest4		0.65
MutPred		0.42		Loss of solvent accessibility (P = 0.0544);Loss of solvent accessibility (P = 0.0544);
MVP		0.88
MPC		0.26
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-176965086; COSMIC: COSV66832933; COSMIC: COSV66832933;