2-176100358-G-A

Variant names:

• chr2-176100358-G-A
• rs35817516
• NM_021193.4:c.557G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021193.4(HOXD12):​c.557G>A​(p.Arg186Gln) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,612,120 control chromosomes in the GnomAD database, including 14,203 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 0.10 (993 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13210 hom.)
• Consequence: HOXD12 NM_021193.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016656518).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.169 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.557G>A	p.Arg186Gln	missense	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.557G>A	p.Arg186Gln	missense	Exon 1 of 2	ENSP00000385586.2
	HOXD12	ENST00000404162.2	TSL:1	c.557G>A	p.Arg186Gln	missense	Exon 1 of 2	ENSP00000385132.2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15321 AN: 152164 Hom.: 992 Cov.: 33

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.00966

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.0998

GnomAD2 exomes AF: 0.121 AC: 29098 AN: 240584 AF XY: 0.117

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.0874

Gnomad EAS exome AF: 0.00903

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.128 AC: 187560 AN: 1459838 Hom.: 13210 Cov.: 33 AF XY: 0.127 AC XY: 92311 AN XY: 726216

African (AFR) AF: 0.0238 AC: 796 AN: 33476

American (AMR) AF: 0.229 AC: 10224 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 2282 AN: 26106

East Asian (EAS) AF: 0.00663 AC: 263 AN: 39698

South Asian (SAS) AF: 0.0791 AC: 6819 AN: 86216

European-Finnish (FIN) AF: 0.103 AC: 5352 AN: 52114

Middle Eastern (MID) AF: 0.0905 AC: 522 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154363 AN: 1111512

Other (OTH) AF: 0.115 AC: 6939 AN: 60300

GnomAD4 genome AF: 0.101 AC: 15320 AN: 152282 Hom.: 993 Cov.: 33 AF XY: 0.100 AC XY: 7458 AN XY: 74464

African (AFR) AF: 0.0319 AC: 1326 AN: 41576

American (AMR) AF: 0.175 AC: 2676 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 325 AN: 3470

East Asian (EAS) AF: 0.00968 AC: 50 AN: 5164

South Asian (SAS) AF: 0.0708 AC: 342 AN: 4832

European-Finnish (FIN) AF: 0.105 AC: 1110 AN: 10606

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9240 AN: 68002

Other (OTH) AF: 0.0992 AC: 210 AN: 2116

Alfa AF: 0.124 Hom.: 2392

Bravo AF: 0.103

TwinsUK AF: 0.142 AC: 528

ALSPAC AF: 0.137 AC: 528

ESP6500AA AF: 0.0310 AC: 110

ESP6500EA AF: 0.118 AC: 912

ExAC AF: 0.112 AC: 13351

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.21	T
Sift4G	Benign	0.16	T
Polyphen		0.51	P
Vest4		0.33
MPC		0.14
ClinPred		0.018	T
GERP RS		4.6
Varity_R		0.21
gMVP		0.61
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35817516; hg19: chr2-176965086; COSMIC: COSV66832842; COSMIC: COSV66832842;