chr2-176092922-G-T

Variant names:

• chr2-176092922-G-T
• rs536639583
• NM_000523.4:c.32G>T

Variant summary

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

The NM_000523.4(HOXD13):​c.32G>T​(p.Gly11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,329,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.282
• Publications: 11 publications found

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]

HOXD13 Gene-Disease associations (from GenCC):

• brachydactyly-syndactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Laboratory for Molecular Medicine, Orphanet
• synpolydactyly type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• brachydactyly type E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 5

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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_000523.4. 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
	HOXD13	NM_000523.4	MANE Select	c.32G>T	p.Gly11Val	missense	Exon 1 of 2	NP_000514.2	P35453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD13	ENST00000392539.4	TSL:1 MANE Select	c.32G>T	p.Gly11Val	missense	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151682 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 8.49e-7 AC: 1 AN: 1177884 Hom.: 0 Cov.: 30 AF XY: 0.00000174 AC XY: 1 AN XY: 575024

African (AFR) AF: 0.00 AC: 0 AN: 23296

American (AMR) AF: 0.00 AC: 0 AN: 13218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17532

East Asian (EAS) AF: 0.00 AC: 0 AN: 25652

South Asian (SAS) AF: 0.00 AC: 0 AN: 46166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3380

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 975526

Other (OTH) AF: 0.00 AC: 0 AN: 47074

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151682 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74078

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.054
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.69	N
PhyloP100		0.28
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.36
MutPred		0.28		Loss of loop (P = 0.0374)
MVP		0.98
ClinPred		0.81	D
GERP RS		2.3
PromoterAI		0.021	Neutral
Varity_R		0.18
gMVP		0.46
Mutation Taster		=84/16	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: rs536639583; hg19: chr2-176957650;