chr2-176123231-G-C

Position:

• chr2-176123231-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014213.4(HOXD9):​c.463G>C​(p.Gly155Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,403,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: HOXD9 NM_014213.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.48

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029539794).
• BP6: Variant 2-176123231-G-C is Benign according to our data. Variant chr2-176123231-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3043845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXD9	NM_014213.4	c.463G>C	p.Gly155Arg	missense_variant	1/2	ENST00000249499.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXD9	ENST00000249499.8	c.463G>C	p.Gly155Arg	missense_variant	1/2	1	NM_014213.4	P1
HOXD-AS2	ENST00000440016.6	n.498-787C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 88 AN: 150062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000916

Gnomad FIN AF: 0.000669

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000826 AC: 66 AN: 79912 Hom.: 0 AF XY: 0.00103 AC XY: 46 AN XY: 44528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000719

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000802

Gnomad OTH exome AF: 0.000466

GnomAD4 exome AF: 0.000871 AC: 1091 AN: 1253066 Hom.: 1 Cov.: 34 AF XY: 0.000962 AC XY: 591 AN XY: 614098

Gnomad4 AFR exome AF: 0.0000812

Gnomad4 AMR exome AF: 0.0000427

Gnomad4 ASJ exome AF: 0.0000548

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.000879

Gnomad4 OTH exome AF: 0.000590

GnomAD4 genome AF: 0.000586 AC: 88 AN: 150200 Hom.: 0 Cov.: 33 AF XY: 0.000613 AC XY: 45 AN XY: 73410

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000200

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000915

Gnomad4 FIN AF: 0.000669

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000219 Hom.: 1

Bravo AF: 0.000453

ExAC AF: 0.000236 AC: 18

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HOXD9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.00030	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.96	D
Vest4		0.37
MutPred		0.55		Gain of methylation at G155 (P = 0.0216);
MVP		0.97
MPC		1.2
ClinPred		0.33	T
GERP RS		2.6
Varity_R		0.52
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs191379716; hg19: chr2-176987959;