2-176123186-G-T

Variant names:

• chr2-176123186-G-T
• rs946500426
• NM_014213.4:c.418G>T

Variant summary

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

The NM_014213.4(HOXD9):​c.418G>T​(p.Gly140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 1,258,362 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. G140S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HOXD9 NM_014213.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.673
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4	c.418G>T	p.Gly140Cys	missense_variant	Exon 1 of 2	ENST00000249499.8	NP_055028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD9	ENST00000249499.8	c.418G>T	p.Gly140Cys	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6
HOXD-AS2	ENST00000440016.6	n.498-742C>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000238 AC: 3 AN: 1258362 Hom.: 0 Cov.: 34 AF XY: 0.00000163 AC XY: 1 AN XY: 614312

African (AFR) AF: 0.00 AC: 0 AN: 24344

American (AMR) AF: 0.00 AC: 0 AN: 13138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17806

East Asian (EAS) AF: 0.000106 AC: 3 AN: 28242

South Asian (SAS) AF: 0.00 AC: 0 AN: 56560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1018484

Other (OTH) AF: 0.00 AC: 0 AN: 51486

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.0093	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.67
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T
Sift4G	Benign	0.091	T
Polyphen		0.99	D
Vest4		0.39
MutPred		0.42		Loss of methylation at R143 (P = 0.111);
MVP		0.95
MPC		1.5
ClinPred		0.41	T
GERP RS		1.9
PromoterAI		-0.018	Neutral
Varity_R		0.17
gMVP		0.58
Mutation Taster		=96/4	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: rs946500426; hg19: chr2-176987914;