Variant chr2-176107587-G-A 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_021192.3(HOXD11):c.232G>A(p.Gly78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000064 in 1,374,716 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 0.000061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

HOXD11
NM_021192.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59

Variant links:

Genes affected

HOXD11 (HGNC:5134): (homeobox D11) 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 product of the mouse Hoxd11 gene plays a role in forelimb morphogenesis. [provided by RefSeq, Jul 2008]

HOXD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2579605).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXD11	NM_021192.3 linkuse as main transcript	c.232G>A	p.Gly78Ser	missense_variant	1/2	ENST00000249504.7	NP_067015.2
HOXD11	XR_007073114.1 linkuse as main transcript	n.308G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXD11	ENST00000249504.7 linkuse as main transcript	c.232G>A	p.Gly78Ser	missense_variant	1/2	3	NM_021192.3	ENSP00000249504	P1
HOXD11	ENST00000498438.1 linkuse as main transcript	n.412-1320G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000606

AC:

AN:

148490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.0000748

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000973

AC:

AN:

113104

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

65400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000160

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:

0.000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000644

AC:

AN:

1226136

Hom.:

Cov.:

AF XY:

0.0000736

AC XY:

AN XY:

597574

show subpopulations

Gnomad4 AFR exome

AF:

0.0000769

Gnomad4 AMR exome

AF:

0.000261

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000204

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000661

Gnomad4 OTH exome

AF:

0.0000614

GnomAD4 genome

AF:

0.0000606

AC:

AN:

148580

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

72528

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000748

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000100

AC:

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

Jan 26, 2023

The c.232G>A (p.G78S) alteration is located in exon 1 (coding exon 1) of the HOXD11 gene. This alteration results from a G to A substitution at nucleotide position 232, causing the glycine (G) at amino acid position 78 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

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.053

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.98

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.19

REVEL

Benign

0.14

Sift

Benign

0.29

Sift4G

Benign

0.46

Polyphen

0.079

Vest4

0.42

MVP

0.83

ClinPred

0.063

GERP RS

2.0

Varity_R

0.094

gMVP

0.34

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