Variant chr2-176189957-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024501.3(HOXD1):c.802C>G(p.Leu268Val) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HOXD1
NM_024501.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

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:

ENSG00000279160 (HGNC:):

ENSG00000279160 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD1	NM_024501.3 link	c.802C>G	p.Leu268Val	missense_variant	2/2	ENST00000331462.6	NP_078777.1	Q9GZZ0Q96CA4
HOXD1	XM_047444086.1 link	c.*122C>G		3_prime_UTR_variant	3/3		XP_047300042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD1	ENST00000331462.6 link	c.802C>G	p.Leu268Val	missense_variant	2/2	1	NM_024501.3	ENSP00000328598.4		Q9GZZ0
ENSG00000279160	ENST00000623777.1 link	n.2582G>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251462

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000924

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000562

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

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

Oct 21, 2021

The c.802C>G (p.L268V) alteration is located in exon 2 (coding exon 2) of the HOXD1 gene. This alteration results from a C to G substitution at nucleotide position 802, causing the leucine (L) at amino acid position 268 to be replaced by a valine (V). 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MVP

0.98

ClinPred

0.43

GERP RS

5.7

Varity_R

0.54

gMVP

0.85

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