chr1-44806188-G-A

Variant names:

• chr1-44806188-G-A
• rs770447442
• NM_001377534.1:c.481C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001377534.1(DYNLT4):​c.481C>T​(p.Arg161Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DYNLT4 NM_001377534.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.481C>T	p.Arg161Cys	missense	Exon 3 of 3	NP_001364463.1	Q5JR98
	DYNLT4	NM_001013632.4		c.481C>T	p.Arg161Cys	missense	Exon 2 of 2	NP_001013654.1	Q5JR98
	DYNLT4	NM_001377535.1		c.481C>T	p.Arg161Cys	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.481C>T	p.Arg161Cys	missense	Exon 3 of 3	ENSP00000341803.2	Q5JR98
	DYNLT4	ENST00000675259.1		c.481C>T	p.Arg161Cys	missense	Exon 2 of 2	ENSP00000501642.1	Q5JR98
	DYNLT4	ENST00000854447.1		c.481C>T	p.Arg161Cys	missense	Exon 3 of 3	ENSP00000524506.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000137 AC: 2 AN: 146300 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000869

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399086 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691576

African (AFR) AF: 0.00 AC: 0 AN: 32222

American (AMR) AF: 0.00 AC: 0 AN: 36348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36688

South Asian (SAS) AF: 0.00 AC: 0 AN: 80558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084052

Other (OTH) AF: 0.0000343 AC: 2 AN: 58248

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.18
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.50		Loss of disorder (P = 0.0277)
MVP		0.31
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.37
gMVP		0.36
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs770447442; hg19: chr1-45271860; COSMIC: COSV105914247; COSMIC: COSV105914247;