Variant rs35817516 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021193.4(HOXD12):c.557G>A(p.Arg186Gln) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,612,120 control chromosomes in the GnomAD database, including 14,203 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.10 ( 993 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13210 hom. )

Consequence

HOXD12
NM_021193.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.59

Variant links:

Genes affected

HOXD12 (HGNC:5135): (homeobox D12) 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 in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 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]

HOXD12 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016656518).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD12	NM_021193.4 link	c.557G>A	p.Arg186Gln	missense_variant	1/2	ENST00000406506.4	NP_067016.3	P35452-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD12	ENST00000406506.4 link	c.557G>A	p.Arg186Gln	missense_variant	1/2	3	NM_021193.4	ENSP00000385586.2		P35452-1
HOXD12	ENST00000404162.2 link	c.557G>A	p.Arg186Gln	missense_variant	1/2	1		ENSP00000385132.2		B5MCD3

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15321

AN:

152164

Hom.:

992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0320

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.0937

Gnomad EAS

AF:

0.00966

Gnomad SAS

AF:

0.0703

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.0998

GnomAD3 exomes

AF:

0.121

AC:

29098

AN:

240584

Hom.:

2284

AF XY:

0.117

AC XY:

15512

AN XY:

132482

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.237

Gnomad ASJ exome

AF:

0.0874

Gnomad EAS exome

AF:

0.00903

Gnomad SAS exome

AF:

0.0769

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.128

AC:

187560

AN:

1459838

Hom.:

13210

Cov.:

AF XY:

0.127

AC XY:

92311

AN XY:

726216

show subpopulations

Gnomad4 AFR exome

AF:

0.0238

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.0874

Gnomad4 EAS exome

AF:

0.00663

Gnomad4 SAS exome

AF:

0.0791

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.139

Gnomad4 OTH exome

AF:

0.115

GnomAD4 genome

AF:

0.101

AC:

15320

AN:

152282

Hom.:

993

Cov.:

AF XY:

0.100

AC XY:

7458

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0319

Gnomad4 AMR

AF:

0.175

Gnomad4 ASJ

AF:

0.0937

Gnomad4 EAS

AF:

0.00968

Gnomad4 SAS

AF:

0.0708

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.136

Gnomad4 OTH

AF:

0.0992

Alfa

AF:

0.126

Hom.:

1828

Bravo

AF:

0.103

TwinsUK

AF:

0.142

AC:

528

ALSPAC

AF:

0.137

AC:

528

ESP6500AA

AF:

0.0310

AC:

110

ESP6500EA

AF:

0.118

AC:

912

ExAC

AF:

0.112

AC:

13351

Asia WGS

AF:

0.0410

AC:

144

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.21

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.51

P;P

Vest4

0.33

MPC

0.14

ClinPred

0.018

GERP RS

4.6

Varity_R

0.21

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over