chr2-176107588-G-A

Variant summary

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

The NM_021192.3(HOXD11):​c.233G>A​(p.Gly78Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000814 in 1,228,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

HOXD11
NM_021192.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HOXD11NM_021192.3 linkuse as main transcriptc.233G>A p.Gly78Asp missense_variant 1/2 ENST00000249504.7 NP_067015.2 P31277
HOXD11XR_007073114.1 linkuse as main transcriptn.309G>A non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HOXD11ENST00000249504.7 linkuse as main transcriptc.233G>A p.Gly78Asp missense_variant 1/23 NM_021192.3 ENSP00000249504.5 P31277
HOXD11ENST00000498438.1 linkuse as main transcriptn.412-1319G>A intron_variant 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
8.14e-7
AC:
1
AN:
1228230
Hom.:
0
Cov.:
32
AF XY:
0.00000167
AC XY:
1
AN XY:
598610
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000102
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 20, 2022The c.233G>A (p.G78D) alteration is located in exon 1 (coding exon 1) of the HOXD11 gene. This alteration results from a G to A substitution at nucleotide position 233, causing the glycine (G) at amino acid position 78 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Uncertain
0.075
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.27
T
Eigen
Benign
-0.039
Eigen_PC
Benign
-0.073
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.35
T
M_CAP
Pathogenic
0.92
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.29
N
REVEL
Uncertain
0.33
Sift
Benign
0.031
D
Sift4G
Benign
0.27
T
Polyphen
0.80
P
Vest4
0.50
MutPred
0.24
Loss of MoRF binding (P = 0.0375);
MVP
0.92
ClinPred
0.32
T
GERP RS
2.9
Varity_R
0.12
gMVP
0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-176972316; API