NM_021192.3:c.95C>G

Variant names:

• chr2-176107450-C-G
• rs747356339
• NM_021192.3:c.95C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021192.3(HOXD11):​c.95C>G​(p.Pro32Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HOXD11 NM_021192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021192.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD11	NM_021192.3	MANE Select	c.95C>G	p.Pro32Arg	missense	Exon 1 of 2	NP_067015.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD11	ENST00000249504.7	TSL:3 MANE Select	c.95C>G	p.Pro32Arg	missense	Exon 1 of 2	ENSP00000249504.5	P31277
	HOXD11	ENST00000498438.1	TSL:1	n.412-1457C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250132 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461758 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.064
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.28		Loss of ubiquitination at K31 (P = 0.0525)
MVP		0.76
ClinPred		0.97	D
GERP RS		1.6
PromoterAI		-0.018	Neutral
Varity_R		0.55
gMVP		0.32
Mutation Taster		=82/18	polymorphism

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: rs747356339; hg19: chr2-176972178;