chr2-176092922-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000523.4(HOXD13):c.32G>C(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,329,670 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

HOXD13
NM_000523.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 0.282

Variant links:

Genes affected

HOXD13 (HGNC:5136): (homeobox D13) 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. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

HOXD13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.118177116).

BP6

Variant 2-176092922-G-C is Benign according to our data. Variant chr2-176092922-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000856 (130/151790) while in subpopulation EAS AF= 0.022 (113/5136). AF 95% confidence interval is 0.0187. There are 1 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4 link	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 2	ENST00000392539.4	NP_000514.2	P35453
HOXD13	XM_011511068.3 link	c.725-1558G>C		intron_variant	Intron 1 of 1		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4 link	c.32G>C	p.Gly11Ala	missense_variant	Exon 1 of 2	1	NM_000523.4	ENSP00000376322.3		P35453

Frequencies

GnomAD3 genomes

AF:

0.000857

AC:

130

AN:

151682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0219

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000185

AC:

AN:

37778

Hom.:

AF XY:

0.000299

AC XY:

AN XY:

23412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00400

Gnomad SAS exome

AF:

0.000660

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000454

AC:

535

AN:

1177880

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

252

AN XY:

575020

show subpopulations

Gnomad4 AFR exome

AF:

0.0000429

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0167

Gnomad4 SAS exome

AF:

0.000693

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000923

Gnomad4 OTH exome

AF:

0.00138

GnomAD4 genome

AF:

0.000856

AC:

130

AN:

151790

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0220

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.00106

ExAC

AF:

0.000528

AC:

Asia WGS

AF:

0.00499

AC:

AN:

3418

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2018	The G11A variant has been published previously in association with a synpolydactyly phenotype; the homozygous proband was more severely affected than the heterozygous mother, but the father's phenotype was not provided (Brison et al., 2012). However, the variant has also been observed in the homozygous state at GeneDx in an individual whose phenotype did not match a HOXD13 presentation. The variant is observed in 3/1714 (0.175%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). G11A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Functional studies have shown that G11A has no effect on DNA binding, transactivation, or localization; however, it speeds protein degradation and led to skeletal abnormalities in chick embryos (Brison et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 10, 2024	- -

Synpolydactyly type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.88

REVEL

Uncertain

0.62

Sift

Benign

0.12

Sift4G

Benign

0.17

Polyphen

0.95

Vest4

0.71

MutPred

0.66

Gain of helix (P = 0.0034);

MVP

0.95

ClinPred

0.16

GERP RS

2.3

Varity_R

0.13

gMVP

0.39

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