1-44806105-G-T

Variant names:

• chr1-44806105-G-T
• rs1295444173
• NM_001377534.1:c.564C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001377534.1(DYNLT4):​c.564C>A​(p.Ser188Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,264 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: 6.9e-7 (0 hom.)
• Consequence: DYNLT4 NM_001377534.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377534.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNLT4	NM_001377534.1	MANE Select	c.564C>A	p.Ser188Arg	missense	Exon 3 of 3	NP_001364463.1	Q5JR98
	DYNLT4	NM_001013632.4		c.564C>A	p.Ser188Arg	missense	Exon 2 of 2	NP_001013654.1	Q5JR98
	DYNLT4	NM_001377535.1		c.564C>A	p.Ser188Arg	missense	Exon 3 of 3	NP_001364464.1	Q5JR98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNLT4	ENST00000339355.3	TSL:6 MANE Select	c.564C>A	p.Ser188Arg	missense	Exon 3 of 3	ENSP00000341803.2	Q5JR98
	DYNLT4	ENST00000675259.1		c.564C>A	p.Ser188Arg	missense	Exon 2 of 2	ENSP00000501642.1	Q5JR98
	DYNLT4	ENST00000854447.1		c.564C>A	p.Ser188Arg	missense	Exon 3 of 3	ENSP00000524506.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456264 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724172

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110124

Other (OTH) AF: 0.0000166 AC: 1 AN: 60114

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.93
MutPred		0.85		Gain of MoRF binding (P = 0.0383)
MVP		0.20
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.81
gMVP		0.72
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1295444173; hg19: chr1-45271777;