NM_000523.4:c.117G>C

Variant names:

• chr2-176093007-G-C
• rs1351023304
• NM_000523.4:c.117G>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.117G>C​(p.Gln39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,385,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: HOXD13 NM_000523.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91
• 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=0.34698611).

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.117G>C	p.Gln39His	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.117G>C	p.Gln39His	missense	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151188 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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000324 AC: 4 AN: 1234372 Hom.: 0 Cov.: 31 AF XY: 0.00000165 AC XY: 1 AN XY: 605958

African (AFR) AF: 0.00 AC: 0 AN: 24142

American (AMR) AF: 0.00 AC: 0 AN: 14076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19464

East Asian (EAS) AF: 0.00 AC: 0 AN: 26744

South Asian (SAS) AF: 0.00 AC: 0 AN: 56252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4504

European-Non Finnish (NFE) AF: 0.00000397 AC: 4 AN: 1008694

Other (OTH) AF: 0.00 AC: 0 AN: 50266

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151188 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73820

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

African (AFR) AF: 0.00 AC: 0 AN: 41300

American (AMR) AF: 0.00 AC: 0 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10316

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67724

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T
Sift4G	Benign	0.45	T
Polyphen		0.38	B
Vest4		0.25
MutPred		0.095		Gain of methylation at R41 (P = 0.0418)
MVP		0.92
ClinPred		0.30	T
GERP RS		3.2
PromoterAI		0.019	Neutral
Varity_R		0.15
gMVP		0.60
Mutation Taster		=85/15	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: rs1351023304; hg19: chr2-176957735;