Genetic Variant HDHD3:p.Asp169Asn (chr9-113373850-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001304509.2(HDHD3):c.505G>A(p.Asp169Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HDHD3
NM_001304509.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

Variant links:

Genes affected

HDHD3 (HGNC:28171): (haloacid dehalogenase like hydrolase domain containing 3) Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

HDHD3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDHD3	NM_001304509.2 link	c.505G>A	p.Asp169Asn	missense_variant	Exon 3 of 3	ENST00000374180.4	NP_001291438.1	Q9BSH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDHD3	ENST00000374180.4 link	c.505G>A	p.Asp169Asn	missense_variant	Exon 3 of 3	1	NM_001304509.2	ENSP00000363295.3	Q9BSH5
HDHD3	ENST00000238379.9 link	c.505G>A	p.Asp169Asn	missense_variant	Exon 2 of 2	1		ENSP00000238379.5	Q9BSH5
HDHD3	ENST00000485934.1 link	n.*38G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251264

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS 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:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505G>A (p.D169N) alteration is located in exon 2 (coding exon 1) of the HDHD3 gene. This alteration results from a G to A substitution at nucleotide position 505, causing the aspartic acid (D) at amino acid position 169 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.23

Sift

Benign

0.10

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.96

D;D

Vest4

0.28

MutPred

0.62

Loss of ubiquitination at K167 (P = 0.0672);Loss of ubiquitination at K167 (P = 0.0672);

MVP

0.67

MPC

0.42

ClinPred

0.79

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over