rs762288646

Variant names:

• chr1-44806232-G-A
• rs762288646
• NM_001377534.1:c.437C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377534.1(DYNLT4):​c.437C>T​(p.Ala146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYNLT4 NM_001377534.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.559
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12722161).

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.437C>T	p.Ala146Val	missense	Exon 3 of 3	NP_001364463.1	Q5JR98
	DYNLT4	NM_001013632.4		c.437C>T	p.Ala146Val	missense	Exon 2 of 2	NP_001013654.1	Q5JR98
	DYNLT4	NM_001377535.1		c.437C>T	p.Ala146Val	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.437C>T	p.Ala146Val	missense	Exon 3 of 3	ENSP00000341803.2	Q5JR98
	DYNLT4	ENST00000675259.1		c.437C>T	p.Ala146Val	missense	Exon 2 of 2	ENSP00000501642.1	Q5JR98
	DYNLT4	ENST00000854447.1		c.437C>T	p.Ala146Val	missense	Exon 3 of 3	ENSP00000524506.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 129598 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1380414 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 680768

African (AFR) AF: 0.00 AC: 0 AN: 31388

American (AMR) AF: 0.00 AC: 0 AN: 35242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 35506

South Asian (SAS) AF: 0.00 AC: 0 AN: 79090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075094

Other (OTH) AF: 0.00 AC: 0 AN: 57554

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000225 AC: 2

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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		0.56
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.10
Sift	Benign	0.051	T
Sift4G	Benign	0.082	T
Polyphen		0.71	P
Vest4		0.13
MutPred		0.40		Loss of disorder (P = 0.0702)
MVP		0.055
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.077
gMVP		0.28
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs762288646; hg19: chr1-45271904;