2-176169569-C-T

Variant names:

• chr2-176169569-C-T
• rs774350237
• NM_006898.5:c.455C>T

Variant summary

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

The NM_006898.5(HOXD3):​c.455C>T​(p.Ser152Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,848 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. S152C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HOXD3 NM_006898.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

Genes affected

HOXD3 (HGNC:5137): (homeobox D3) 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 at 2q31-2q37 chromosome regions. Deletions that removed the entire HOXD gene cluster or 5' end of this cluster have been associated with severe limb and genital abnormalities. The protein encoded by this gene may play a role in the regulation of cell adhesion processes. [provided by RefSeq, Jul 2008]

HAGLR (HGNC:43755): (HOXD antisense growth-associated long non-coding RNA)

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_006898.5. 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
	HOXD3	NM_006898.5	MANE Select	c.455C>T	p.Ser152Phe	missense	Exon 3 of 4	NP_008829.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD3	ENST00000683222.1	MANE Select	c.455C>T	p.Ser152Phe	missense	Exon 3 of 4	ENSP00000507129.1	P31249
	HOXD3	ENST00000249440.4	TSL:1	c.455C>T	p.Ser152Phe	missense	Exon 2 of 3	ENSP00000249440.2	P31249
	HOXD3	ENST00000410016.5	TSL:5	c.455C>T	p.Ser152Phe	missense	Exon 2 of 3	ENSP00000386498.1	P31249

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250766 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.27		Loss of phosphorylation at S152 (P = 0.0131)
MVP		0.94
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.62
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774350237; hg19: chr2-177034297;