1-44806020-C-T

Position:

• chr1-44806020-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001377534.1(DYNLT4):​c.649G>A​(p.Gly217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,411,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYNLT4 NM_001377534.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

DYNLT4 (HGNC:32315): (dynein light chain Tctex-type 4) Enables protein phosphatase 1 binding activity. Predicted to be involved in microtubule-based movement. Located in acrosomal vesicle; cytoskeleton; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

PLK3 (HGNC:2154): (polo like kinase 3) The protein encoded by this gene is a member of the highly conserved polo-like kinase family of serine/threonine kinases. Members of this family are characterized by an amino-terminal kinase domain and a carboxy-terminal bipartite polo box domain that functions as a substrate-binding motif and a cellular localization signal. Polo-like kinases are important regulators of cell cycle progression. This gene has also been implicated in stress responses and double-strand break repair. In human cell lines, this protein is reported to associate with centrosomes in a microtubule-dependent manner, and during mitosis, the protein becomes localized to the mitotic apparatus. Expression of a kinase-defective mutant results in abnormal cell morphology caused by changes in microtubule dynamics and mitotic arrest followed by apoptosis. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNLT4	NM_001377534.1	c.649G>A	p.Gly217Arg	missense_variant	3/3	ENST00000339355.3	NP_001364463.1
PLK3	NM_004073.4	c.*342C>T		downstream_gene_variant		ENST00000372201.5	NP_004064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNLT4	ENST00000339355.3	c.649G>A	p.Gly217Arg	missense_variant	3/3	6	NM_001377534.1	ENSP00000341803.2
DYNLT4	ENST00000675259.1	c.649G>A	p.Gly217Arg	missense_variant	2/2			ENSP00000501642.1
PLK3	ENST00000372201.5	c.*342C>T		downstream_gene_variant		1	NM_004073.4	ENSP00000361275.4
PLK3	ENST00000465443.5	n.*30C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1411792 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 15, 2023

The c.649G>A (p.G217R) alteration is located in exon 2 (coding exon 1) of the TCTEX1D4 gene. This alteration results from a G to A substitution at nucleotide position 649, causing the glycine (G) at amino acid position 217 to be replaced by an arginine (R). 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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.95	P
Vest4		0.83
MutPred		0.79		Gain of methylation at G217 (P = 0.0572);
MVP		0.32
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs775950000; hg19: chr1-45271692;