7-44485075-C-G

Position:

• chr7-44485075-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015332.4(NUDCD3):​c.402G>C​(p.Gln134His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NUDCD3 NM_015332.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060814947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDCD3	NM_015332.4	c.402G>C	p.Gln134His	missense_variant	2/6	ENST00000355451.8	NP_056147.2
NUDCD3	XM_011515247.3	c.402G>C	p.Gln134His	missense_variant	2/6		XP_011513549.1
NUDCD3	XM_017011908.2	c.402G>C	p.Gln134His	missense_variant	2/4		XP_016867397.1
NUDCD3	XR_007059994.1	n.460G>C		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDCD3	ENST00000355451.8	c.402G>C	p.Gln134His	missense_variant	2/6	1	NM_015332.4	ENSP00000347626.6
NUDCD3	ENST00000464812.1	n.500G>C		non_coding_transcript_exon_variant	3/5	5
NUDCD3	ENST00000480209.1	n.200G>C		non_coding_transcript_exon_variant	1/2	3
NUDCD3	ENST00000497978.1	n.653G>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The c.402G>C (p.Q134H) alteration is located in exon 2 (coding exon 2) of the NUDCD3 gene. This alteration results from a G to C substitution at nucleotide position 402, causing the glutamine (Q) at amino acid position 134 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	0.087
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.058
Sift	Benign	0.12	T
Sift4G	Uncertain	0.047	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.14		Loss of helix (P = 0.0304);
MVP		0.25
MPC		0.23
ClinPred		0.034	T
GERP RS		-1.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.15
gMVP		0.15

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

Other links and lift over

dbSNP: rs115164631; hg19: chr7-44524674;