Variant 2-176151875-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014621.3(HOXD4):c.242A>T(p.Glu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,585,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

HOXD4
NM_014621.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.80

Variant links:

Genes affected

HOXD4 (HGNC:5138): (homeobox D4) 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 protein encoded by this gene may play a role in determining positional values in developing limb buds. Alternatively spliced variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

HOXD4 links:

HOXD3 (HGNC:5137): (homeobox D3) 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 protein encoded by this gene may play a role in the regulation of cell adhesion processes. [provided by RefSeq, Jul 2008]

HOXD3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21931592).

BS2

High AC in GnomAd4 at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD4	NM_014621.3 linkuse as main transcript	c.242A>T	p.Glu81Val	missense_variant	1/2	ENST00000306324.4	NP_055436.2	P09016

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD4	ENST00000306324.4 linkuse as main transcript	c.242A>T	p.Glu81Val	missense_variant	1/2	1	NM_014621.3	ENSP00000302548.3		P09016
HOXD3	ENST00000432796.2 linkuse as main transcript	c.-85+14876A>T		intron_variant		3		ENSP00000392615.2		C9J1M3

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

130

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000791

AC:

152

AN:

192114

Hom.:

AF XY:

0.000710

AC XY:

AN XY:

105706

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.000443

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00128

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.00149

AC:

2131

AN:

1433096

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

999

AN XY:

710238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000610

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000742

Gnomad4 NFE exome

AF:

0.00181

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000854

AC:

130

AN:

152198

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000774

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Leukemia, acute lymphoblastic, susceptibility to

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.15

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.46

Sift

Benign

0.24

Sift4G

Benign

0.26

Polyphen

0.11

Vest4

0.80

MVP

0.87

MPC

0.50

ClinPred

0.058

GERP RS

3.1

Varity_R

0.15

gMVP

0.41

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