2-176122788-G-A

Variant names:

• chr2-176122788-G-A
• rs186057872
• NM_014213.4:c.20G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014213.4(HOXD9):​c.20G>A​(p.Gly7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,525,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: HOXD9 NM_014213.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017316848).
• BS2: High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD9	NM_014213.4	c.20G>A	p.Gly7Glu	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.20G>A	p.Gly7Glu	missense_variant	Exon 1 of 2	1	NM_014213.4	ENSP00000249499.6
HOXD-AS2	ENST00000440016.6	n.498-344C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000289 AC: 50 AN: 173004 AF XY: 0.000288

Gnomad AFR exome AF: 0.000270

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00350

Gnomad EAS exome AF: 0.000419

Gnomad FIN exome AF: 0.0000523

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00129

GnomAD4 exome AF: 0.000210 AC: 288 AN: 1373166 Hom.: 0 Cov.: 33 AF XY: 0.000224 AC XY: 152 AN XY: 678708

African (AFR) AF: 0.000180 AC: 5 AN: 27734

American (AMR) AF: 0.000132 AC: 4 AN: 30222

Ashkenazi Jewish (ASJ) AF: 0.00389 AC: 81 AN: 20796

East Asian (EAS) AF: 0.000286 AC: 10 AN: 34938

South Asian (SAS) AF: 0.0000826 AC: 6 AN: 72602

European-Finnish (FIN) AF: 0.0000774 AC: 4 AN: 51704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 0.000154 AC: 165 AN: 1073364

Other (OTH) AF: 0.000230 AC: 13 AN: 56404

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74326

African (AFR) AF: 0.000290 AC: 12 AN: 41436

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68014

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

Alfa AF: 0.000558 Hom.: 0

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20G>A (p.G7E) alteration is located in exon 1 (coding exon 1) of the HOXD9 gene. This alteration results from a G to A substitution at nucleotide position 20, causing the glycine (G) at amino acid position 7 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.32	T
Polyphen		0.10	B
Vest4		0.15
MutPred		0.17		Loss of MoRF binding (P = 0.0262);
MVP		0.86
MPC		0.69
ClinPred		0.0070	T
GERP RS		3.4
PromoterAI		0.0088	Neutral
Varity_R		0.13
gMVP		0.13
Mutation Taster		=95/5	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: rs186057872; hg19: chr2-176987516;