chr2-176123186-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014213.4(HOXD9):​c.418G>A​(p.Gly140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,410,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: HOXD9 NM_014213.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23484504).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.418G>A	p.Gly140Ser	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.418G>A	p.Gly140Ser	missense	Exon 1 of 2	ENSP00000249499.6	P28356
	HOXD-AS2	ENST00000440016.6	TSL:5	n.498-742C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152078 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000397 AC: 5 AN: 1258362 Hom.: 0 Cov.: 34 AF XY: 0.00000814 AC XY: 5 AN XY: 614312

African (AFR) AF: 0.0000411 AC: 1 AN: 24344

American (AMR) AF: 0.0000761 AC: 1 AN: 13138

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 28242

South Asian (SAS) AF: 0.0000177 AC: 1 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: 0.00000196 AC: 2 AN: 1018484

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

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.67
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Benign	0.40	T
Sift4G	Benign	0.23	T
Polyphen		0.059	B
Vest4		0.28
MutPred		0.40		Gain of phosphorylation at G140 (P = 6e-04)
MVP		0.86
MPC		1.4
ClinPred		0.18	T
GERP RS		1.9
PromoterAI		0.020	Neutral
Varity_R		0.079
gMVP		0.45
Mutation Taster		=97/3	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;