2-176107678-C-G

Variant names:

• chr2-176107678-C-G
• rs1408115420
• NM_021192.3:c.323C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021192.3(HOXD11):​c.323C>G​(p.Ala108Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 145,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
• Consequence: HOXD11 NM_021192.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25208205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD11	NM_021192.3	c.323C>G	p.Ala108Gly	missense_variant	Exon 1 of 2	ENST00000249504.7	NP_067015.2
HOXD11	XR_007073114.1	n.399C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD11	ENST00000249504.7	c.323C>G	p.Ala108Gly	missense_variant	Exon 1 of 2	3	NM_021192.3	ENSP00000249504.5
HOXD11	ENST00000498438.1	n.412-1229C>G		intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes AF: 0.00000688 AC: 1 AN: 145422 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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 25

GnomAD4 genome AF: 0.00000688 AC: 1 AN: 145422 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 70638

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.23
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.017	B
Vest4		0.16
MutPred		0.22		Loss of helix (P = 0.0376);
MVP		0.89
ClinPred		0.19	T
GERP RS		1.4
Varity_R		0.12
gMVP		0.22

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: rs1408115420; hg19: chr2-176972406;