2-176123226-C-A

Variant names:

• chr2-176123226-C-A
• rs769173326
• NM_014213.4:c.458C>A

Variant summary

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

The NM_014213.4(HOXD9):​c.458C>A​(p.Ala153Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,314,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. A153G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: HOXD9 NM_014213.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 0 publications found

Genes affected

HOXD9 (HGNC:5140): (homeobox D9) 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 exact role of this gene has not been determined. [provided by RefSeq, Jul 2008]

HOXD-AS2 (HGNC:43756): (HOXD cluster antisense RNA 2)

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=0.28358218).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014213.4. 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
	HOXD9	NM_014213.4	MANE Select	c.458C>A	p.Ala153Asp	missense	Exon 1 of 2	NP_055028.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD9	ENST00000249499.8	TSL:1 MANE Select	c.458C>A	p.Ala153Asp	missense	Exon 1 of 2	ENSP00000249499.6	P28356
	HOXD-AS2	ENST00000440016.6	TSL:5	n.498-782G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314108 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 643330

African (AFR) AF: 0.00 AC: 0 AN: 26320

American (AMR) AF: 0.00 AC: 0 AN: 25266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21456

East Asian (EAS) AF: 0.00 AC: 0 AN: 29380

South Asian (SAS) AF: 0.0000146 AC: 1 AN: 68332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1037750

Other (OTH) AF: 0.00 AC: 0 AN: 53996

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Benign	0.065	T
Sift4G	Benign	0.22	T
Polyphen		0.037	B
Vest4		0.25
MutPred		0.35		Loss of MoRF binding (P = 0.0617)
MVP		0.91
MPC		0.90
ClinPred		0.40	T
GERP RS		2.6
Varity_R		0.28
gMVP		0.51
Mutation Taster		=80/20	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: rs769173326; hg19: chr2-176987954;