Genetic Variant HDDC3:p.Trp138* (chr15-90931401-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001286451.2(HDDC3):c.414G>A(p.Trp138*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00512 in 1,582,088 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0034 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 21 hom. )

Consequence

HDDC3
NM_001286451.2 stop_gained

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.84

Publications

4 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 15-90931401-C-T is Benign according to our data. Variant chr15-90931401-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2645716.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286451.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDDC3	NM_001286451.2	MANE Select	c.414G>A	p.Trp138*	stop_gained	Exon 4 of 4	NP_001273380.1	Q8N4P3-1
HDDC3	NM_198527.4		c.*142G>A		3_prime_UTR	Exon 4 of 4	NP_940929.1	Q8N4P3-2
UNC45A	NM_001039675.2		c.-760+1146C>T		intron	N/A	NP_001034764.1	Q9H3U1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDDC3	ENST00000394272.8	TSL:2 MANE Select	c.414G>A	p.Trp138*	stop_gained	Exon 4 of 4	ENSP00000377814.4	Q8N4P3-1
HDDC3	ENST00000559898.5	TSL:1	c.*280G>A		3_prime_UTR	Exon 3 of 3	ENSP00000454103.1	H0YNP9
HDDC3	ENST00000330334.7	TSL:1	c.*142G>A		3_prime_UTR	Exon 4 of 4	ENSP00000330721.3	Q8N4P3-2

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00287

AC:

585

AN:

203856

AF XY:

0.00287

show subpopulations

Gnomad AFR exome

AF:

0.000700

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.000213

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00556

Gnomad OTH exome

AF:

0.00241

GnomAD4 exome

AF:

0.00530

AC:

7582

AN:

1429816

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

3623

AN XY:

708756

show subpopulations

African (AFR)

AF:

0.000803

AC:

AN:

32390

American (AMR)

AF:

0.00169

AC:

AN:

39146

Ashkenazi Jewish (ASJ)

AF:

0.000467

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

37406

South Asian (SAS)

AF:

0.000350

AC:

AN:

82878

European-Finnish (FIN)

AF:

0.00212

AC:

110

AN:

51988

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00647

AC:

7086

AN:

1095302

Other (OTH)

AF:

0.00415

AC:

246

AN:

59258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

430

859

1289

1718

2148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00337

AC:

513

AN:

152272

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41560

American (AMR)

AF:

0.00157

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00610

AC:

415

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00442

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00597

AC:

ExAC

AF:

0.00266

AC:

320

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

PhyloP100

6.8

Vest4

0.20

GERP RS

4.5

Mutation Taster

=114/86

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over