2-176092948-G-C

Position:

• chr2-176092948-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000523.4(HOXD13):​c.58G>C​(p.Gly20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

Genes affected

HOXD13 (HGNC:5136): (homeobox D13) 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. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41161153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD13	NM_000523.4	c.58G>C	p.Gly20Arg	missense_variant	1/2	ENST00000392539.4	NP_000514.2
HOXD13	XM_011511068.3	c.725-1532G>C		intron_variant			XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4	c.58G>C	p.Gly20Arg	missense_variant	1/2	1	NM_000523.4	ENSP00000376322.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1176548 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 573650

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.58G>C (p.G20R) alteration is located in exon 1 (coding exon 1) of the HOXD13 gene. This alteration results from a G to C substitution at nucleotide position 58, causing the glycine (G) at amino acid position 20 to be replaced by an arginine (R). 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	0.45
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.72	P
Vest4		0.30
MutPred		0.22		Gain of methylation at G20 (P = 0.0026);
MVP		0.85
ClinPred		0.35	T
GERP RS		0.62
Varity_R		0.095
gMVP		0.29

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: chr2-176957676;