Genetic Variant NM_000523.4:c.177_182dupGGCGGC (chr2-176093057-G-GGGCGGC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_000523.4(HOXD13):c.177_182dupGGCGGC(p.Ala60_Ala61dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,369,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.191

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

brachydactyly-syndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, G2P
synpolydactyly type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
brachydactyly type E
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 5
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HOXD13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000523.4

BS2

High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000523.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD13	NM_000523.4	MANE Select	c.177_182dupGGCGGC	p.Ala60_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2	NP_000514.2	P35453

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXD13	ENST00000392539.4	TSL:1 MANE Select	c.177_182dupGGCGGC	p.Ala60_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000376322.3	P35453

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

150788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000890

Gnomad OTH

AF:

0.000485

GnomAD2 exomes

AF:

0.0000929

AC:

AN:

21526

AF XY:

0.0000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

144

AN:

1219022

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

595804

show subpopulations

African (AFR)

AF:

0.0000833

AC:

AN:

24022

American (AMR)

AF:

0.0000947

AC:

AN:

10562

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

16990

East Asian (EAS)

AF:

0.00

AC:

AN:

28024

South Asian (SAS)

AF:

0.00

AC:

AN:

50160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4814

European-Non Finnish (NFE)

AF:

0.0000727

AC:

AN:

1003628

Other (OTH)

AF:

0.000320

AC:

AN:

50022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000139

AC:

AN:

150788

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41248

American (AMR)

AF:

0.000198

AC:

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000890

AC:

AN:

67450

Other (OTH)

AF:

0.000485

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over