Genetic Variant HDDC3:p.Arg20Pro (chr15-90932482-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001286451.2(HDDC3):c.59G>C(p.Arg20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,308,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

HDDC3
NM_001286451.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.510

Publications

0 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1871438).

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.59G>C	p.Arg20Pro	missense	Exon 1 of 4	NP_001273380.1	Q8N4P3-1
HDDC3	NM_198527.4		c.59G>C	p.Arg20Pro	missense	Exon 1 of 4	NP_940929.1	Q8N4P3-2
UNC45A	NM_001039675.2		c.-759-1495C>G		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.59G>C	p.Arg20Pro	missense	Exon 1 of 4	ENSP00000377814.4	Q8N4P3-1
HDDC3	ENST00000559898.5	TSL:1	c.59G>C	p.Arg20Pro	missense	Exon 1 of 3	ENSP00000454103.1	H0YNP9
HDDC3	ENST00000330334.7	TSL:1	c.59G>C	p.Arg20Pro	missense	Exon 1 of 4	ENSP00000330721.3	Q8N4P3-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000313

AC:

AN:

31986

AF XY:

0.0000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000390

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000251

AC:

AN:

1155934

Hom.:

Cov.:

AF XY:

0.0000378

AC XY:

AN XY:

555416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24358

American (AMR)

AF:

0.00

AC:

AN:

11610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15558

East Asian (EAS)

AF:

0.000420

AC:

AN:

28590

South Asian (SAS)

AF:

0.000294

AC:

AN:

37456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3166

European-Non Finnish (NFE)

AF:

0.00000208

AC:

AN:

960942

Other (OTH)

AF:

0.0000859

AC:

AN:

46592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000282

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.011

FATHMM_MKL

Benign

0.27

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.9

PhyloP100

0.51

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.27

Sift

Uncertain

0.010

Sift4G

Uncertain

0.037

Polyphen

0.77

Vest4

0.46

MutPred

0.44

Loss of MoRF binding (P = 6e-04)

MVP

0.56

MPC

1.1

ClinPred

0.71

GERP RS

3.1

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.86

gMVP

0.76

Mutation Taster

=51/49

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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