rs775950000

Variant names:

• chr1-44806020-C-T
• rs775950000
• NM_001377534.1:c.649G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-44806020-C-T
• chr1-44806020-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 4 ACMG points.

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

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.649G>A	p.Gly217Arg	missense	Exon 3 of 3	NP_001364463.1	Q5JR98
	DYNLT4	NM_001013632.4		c.649G>A	p.Gly217Arg	missense	Exon 2 of 2	NP_001013654.1	Q5JR98
	DYNLT4	NM_001377535.1		c.649G>A	p.Gly217Arg	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.649G>A	p.Gly217Arg	missense	Exon 3 of 3	ENSP00000341803.2	Q5JR98
	DYNLT4	ENST00000675259.1		c.649G>A	p.Gly217Arg	missense	Exon 2 of 2	ENSP00000501642.1	Q5JR98
	DYNLT4	ENST00000854447.1		c.649G>A	p.Gly217Arg	missense	Exon 3 of 3	ENSP00000524506.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32334

American (AMR) AF: 0.00 AC: 0 AN: 39024

Ashkenazi Jewish (ASJ) AF: 0.0000427 AC: 1 AN: 23410

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 79856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083548

Other (OTH) AF: 0.00 AC: 0 AN: 58212

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	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
PhyloP100		3.2
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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs775950000; hg19: chr1-45271692;