NM_000523.4:c.164G>C

Variant names:

• chr2-176093054-G-C
• rs1443225761
• NM_000523.4:c.164G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000523.4(HOXD13):​c.164G>C​(p.Gly55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000818 in 1,223,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G55R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 0 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: Orphanet, Laboratory for Molecular Medicine, G2P
• synpolydactyly type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31749454).

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.164G>C	p.Gly55Ala	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.164G>C	p.Gly55Ala	missense	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.18e-7 AC: 1 AN: 1223048 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 597788

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

African (AFR) AF: 0.00 AC: 0 AN: 24116

American (AMR) AF: 0.00 AC: 0 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16948

East Asian (EAS) AF: 0.00 AC: 0 AN: 28042

South Asian (SAS) AF: 0.00 AC: 0 AN: 50544

European-Finnish (FIN) AF: 0.0000327 AC: 1 AN: 30564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4818

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007230

Other (OTH) AF: 0.00 AC: 0 AN: 50238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.23
Sift	Benign	0.21	T
Sift4G	Benign	0.47	T
Polyphen		0.025	B
Vest4		0.20
MutPred		0.30		Gain of helix (P = 0.0078)
MVP		0.90
ClinPred		0.094	T
GERP RS		3.4
PromoterAI		-0.052	Neutral
Varity_R		0.095
gMVP		0.41
Mutation Taster		=89/11	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: rs1443225761; hg19: chr2-176957782;