2-176169547-G-C

Variant names:

• chr2-176169547-G-C
• rs749119115
• NM_006898.5:c.433G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006898.5(HOXD3):​c.433G>C​(p.Gly145Arg) 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. 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. G145S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOXD3 NM_006898.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26321608).

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.433G>C	p.Gly145Arg	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.433G>C	p.Gly145Arg	missense	Exon 3 of 4	ENSP00000507129.1	P31249
	HOXD3	ENST00000249440.4	TSL:1	c.433G>C	p.Gly145Arg	missense	Exon 2 of 3	ENSP00000249440.2	P31249
	HOXD3	ENST00000410016.5	TSL:5	c.433G>C	p.Gly145Arg	missense	Exon 2 of 3	ENSP00000386498.1	P31249

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.0037
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.83
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.26	T
Sift4G	Benign	0.54	T
Polyphen		0.45	B
Vest4		0.38
MutPred		0.27		Gain of MoRF binding (P = 0.0101)
MVP		0.95
ClinPred		0.80	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.26
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs749119115; hg19: chr2-177034275;