Variant 2-176189183-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024501.3(HOXD1):c.382G>A(p.Gly128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000765 in 1,568,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

HOXD1
NM_024501.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.665

Variant links:

Genes affected

HOXD1 (HGNC:5132): (homeobox D1) This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. This nuclear protein functions as a sequence-specific transcription factor that is involved in differentiation and limb development. Mutations in this gene have been associated with severe developmental defects on the anterior-posterior (a-p) limb axis. [provided by RefSeq, Jul 2008]

HOXD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09131116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD1	NM_024501.3 link	c.382G>A	p.Gly128Ser	missense_variant	1/2	ENST00000331462.6	NP_078777.1	Q9GZZ0Q96CA4
HOXD1	XM_047444086.1 link	c.382G>A	p.Gly128Ser	missense_variant	1/3		XP_047300042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD1	ENST00000331462.6 link	c.382G>A	p.Gly128Ser	missense_variant	1/2	1	NM_024501.3	ENSP00000328598.4		Q9GZZ0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000589

AC:

AN:

169652

Hom.:

AF XY:

0.0000107

AC XY:

AN XY:

93606

show subpopulations

Gnomad AFR exome

AF:

0.000111

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000424

AC:

AN:

1416578

Hom.:

Cov.:

AF XY:

0.00000570

AC XY:

AN XY:

701226

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.382G>A (p.G128S) alteration is located in exon 1 (coding exon 1) of the HOXD1 gene. This alteration results from a G to A substitution at nucleotide position 382, causing the glycine (G) at amino acid position 128 to be replaced by a serine (S). 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

0.067

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.4

DANN

Benign

0.96

DEOGEN2

Benign

0.023

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.86

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.27

REVEL

Benign

0.15

Sift

Benign

0.58

Sift4G

Benign

0.80

Polyphen

0.023

Vest4

0.21

MutPred

0.31

Gain of glycosylation at G128 (P = 0.0136);

MVP

0.71

ClinPred

0.017

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.055

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over