Genetic Variant NUDCD3:p.Arg45His (chr7-44490467-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015332.4(NUDCD3):c.134G>A(p.Arg45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 0.0000034 ( 0 hom. )

Consequence

NUDCD3
NM_015332.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.16

Variant links:

Genes affected

NUDCD3 (HGNC:22208): (NudC domain containing 3) The product of this gene functions to maintain the stability of dynein intermediate chain. Depletion of this gene product results in aggregation and degradation of dynein intermediate chain, mislocalization of the dynein complex from kinetochores, spindle microtubules, and spindle poles, and loss of gamma-tubulin from spindle poles. The protein localizes to the Golgi apparatus during interphase, and levels of the protein increase after the G1/S transition. [provided by RefSeq, Jul 2008]

NUDCD3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24120241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDCD3	NM_015332.4 link	c.134G>A	p.Arg45His	missense_variant	Exon 1 of 6	ENST00000355451.8	NP_056147.2	Q8IVD9
NUDCD3	XM_011515247.3 link	c.134G>A	p.Arg45His	missense_variant	Exon 1 of 6		XP_011513549.1
NUDCD3	XM_017011908.2 link	c.134G>A	p.Arg45His	missense_variant	Exon 1 of 4		XP_016867397.1
NUDCD3	XR_007059994.1 link	n.192G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUDCD3	ENST00000355451.8 link	c.134G>A	p.Arg45His	missense_variant	Exon 1 of 6	1	NM_015332.4	ENSP00000347626.6	Q8IVD9
NUDCD3	ENST00000464812.1 link	n.140G>A		non_coding_transcript_exon_variant	Exon 1 of 5	5
NUDCD3	ENST00000497978.1 link	n.-202G>A		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

229456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000239

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1451518

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000231

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000767

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134G>A (p.R45H) alteration is located in exon 1 (coding exon 1) of the NUDCD3 gene. This alteration results from a G to A substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a histidine (H). 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

0.099

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.037

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.44

REVEL

Benign

0.072

Sift

Benign

0.29

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.14

MutPred

0.40

Loss of MoRF binding (P = 0.0449);

MVP

0.62

MPC

0.94

ClinPred

0.56

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.21

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