Genetic Variant NM_001286451.2:c.*269A>G (chr15-90931006-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001286451.2(HDDC3):c.*269A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 432,316 control chromosomes in the GnomAD database, including 19,312 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 0.28 ( 6424 hom., cov: 32)

Exomes 𝑓: 0.29 ( 12888 hom. )

Consequence

HDDC3
NM_001286451.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.239

Publications

19 publications found

Variant links:

Genes affected

HDDC3 (HGNC:30522): (HD domain containing 3) Predicted to enable guanosine-3',5'-bis(diphosphate) 3'-diphosphatase activity. [provided by Alliance of Genome Resources, Apr 2022]

HDDC3 links:

UNC45A (HGNC:30594): (unc-45 myosin chaperone A) This gene encodes a regulatory component of the progesterone receptor/heat shock protein 90 chaperoning complex, which functions in the assembly and folding of the progesterone receptor. The encoded protein is thought to be essential for normal cell proliferation, and for the accumulation of myosin during development of muscle cells. [provided by RefSeq, Sep 2018]

UNC45A Gene-Disease associations (from GenCC):

osteootohepatoenteric syndrome
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

UNC45A links:

Genome browser will be placed here

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=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDDC3	NM_001286451.2 link	c.*269A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000394272.8	NP_001273380.1	Q8N4P3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDDC3	ENST00000394272.8 link	c.*269A>G		3_prime_UTR_variant	Exon 4 of 4	2	NM_001286451.2	ENSP00000377814.4		Q8N4P3-1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42662

AN:

151928

Hom.:

6421

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.573

Gnomad SAS

AF:

0.265

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.303

GnomAD4 exome

AF:

0.289

AC:

80873

AN:

280270

Hom.:

12888

Cov.:

AF XY:

0.287

AC XY:

42517

AN XY:

148228

show subpopulations

African (AFR)

AF:

0.215

AC:

1954

AN:

9078

American (AMR)

AF:

0.355

AC:

4063

AN:

11448

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

2028

AN:

8568

East Asian (EAS)

AF:

0.562

AC:

9430

AN:

16792

South Asian (SAS)

AF:

0.259

AC:

8658

AN:

33440

European-Finnish (FIN)

AF:

0.270

AC:

4223

AN:

15654

Middle Eastern (MID)

AF:

0.286

AC:

339

AN:

1186

European-Non Finnish (NFE)

AF:

0.271

AC:

45421

AN:

167882

Other (OTH)

AF:

0.293

AC:

4757

AN:

16222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2636

5272

7909

10545

13181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.281

AC:

42686

AN:

152046

Hom.:

6424

Cov.:

AF XY:

0.285

AC XY:

21143

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.220

AC:

9113

AN:

41460

American (AMR)

AF:

0.354

AC:

5400

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

804

AN:

3470

East Asian (EAS)

AF:

0.572

AC:

2958

AN:

5172

South Asian (SAS)

AF:

0.265

AC:

1275

AN:

4816

European-Finnish (FIN)

AF:

0.291

AC:

3077

AN:

10568

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19083

AN:

67972

Other (OTH)

AF:

0.305

AC:

645

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1555

3109

4664

6218

7773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.276

Hom.:

9329

Bravo

AF:

0.288

Asia WGS

AF:

0.443

AC:

1535

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.5

(source)

DANN

Benign

0.58

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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