Genetic Variant HOXD3:c.-85+13243G>T (chr2-176150242-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000432796.2(HOXD3):c.-85+13243G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 493,164 control chromosomes in the GnomAD database, including 41,966 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.

Frequency

Genomes: 𝑓 0.30 ( 8733 hom., cov: 32)

Exomes 𝑓: 0.42 ( 33233 hom. )

Consequence

HOXD3
ENST00000432796.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.807

Publications

13 publications found

Variant links:

COSMIC-nc: COSV60460544

Genes affected

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:

MIR10B (HGNC:31498): (microRNA 10b) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR10B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect
MIR10B	NR_029609.1 link	n.-61G>T	upstream_gene_variant
MIR10B	unassigned_transcript_507	n.-87G>T	upstream_gene_variant
MIR10B	unassigned_transcript_508	n.-126G>T	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD3	ENST00000432796.2 link	c.-85+13243G>T		intron_variant	Intron 1 of 1	3		ENSP00000392615.2
MIR10B	ENST00000385011.1 link	n.-61G>T		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45927

AN:

151936

Hom.:

8720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0990

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.465

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.628

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.310

GnomAD4 exome

AF:

0.415

AC:

141675

AN:

341112

Hom.:

33233

AF XY:

0.428

AC XY:

82234

AN XY:

192320

show subpopulations

African (AFR)

AF:

0.0982

AC:

904

AN:

9202

American (AMR)

AF:

0.638

AC:

20862

AN:

32714

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

2633

AN:

10912

East Asian (EAS)

AF:

0.645

AC:

7606

AN:

11800

South Asian (SAS)

AF:

0.585

AC:

36844

AN:

63012

European-Finnish (FIN)

AF:

0.391

AC:

11944

AN:

30568

Middle Eastern (MID)

AF:

0.353

AC:

653

AN:

1848

European-Non Finnish (NFE)

AF:

0.330

AC:

54905

AN:

166348

Other (OTH)

AF:

0.362

AC:

5324

AN:

14708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

3884

7768

11651

15535

19419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.302

AC:

45942

AN:

152052

Hom.:

8733

Cov.:

AF XY:

0.315

AC XY:

23383

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0987

AC:

4096

AN:

41504

American (AMR)

AF:

0.466

AC:

7117

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

829

AN:

3470

East Asian (EAS)

AF:

0.628

AC:

3228

AN:

5144

South Asian (SAS)

AF:

0.593

AC:

2855

AN:

4812

European-Finnish (FIN)

AF:

0.402

AC:

4246

AN:

10570

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.331

AC:

22469

AN:

67966

Other (OTH)

AF:

0.310

AC:

655

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1480

2961

4441

5922

7402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.313

Hom.:

1148

Bravo

AF:

0.296

Asia WGS

AF:

0.566

AC:

1970

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.81

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over