19-45345698-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177417.3(KLC3):c.157G>A(p.Ala53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,417,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A53V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: KLC3 NM_177417.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409

Genes affected

KLC3 (HGNC:20717): (kinesin light chain 3) This gene encodes a member of the kinesin light chain gene family. Kinesins are molecular motors involved in the transport of cargo along microtubules, and are composed of two kinesin heavy chain (KHC) and two kinesin light chain (KLC) molecules. KLCs are thought to typically be involved in binding cargo and regulating kinesin activity. In the rat, a protein similar to this gene product is expressed in post-meiotic spermatids, where it associates with structural components of sperm tails and mitochondria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06987327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLC3	NM_177417.3	c.157G>A	p.Ala53Thr	missense_variant	2/13	ENST00000391946.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLC3	ENST00000391946.7	c.157G>A	p.Ala53Thr	missense_variant	2/13	1	NM_177417.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000176 AC: 3 AN: 170512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 91952

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1417752 Hom.: 0 Cov.: 32 AF XY: 0.00000571 AC XY: 4 AN XY: 701130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000147

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000260 AC: 3

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

Sep 23, 2023

The c.157G>A (p.A53T) alteration is located in exon 2 (coding exon 1) of the KLC3 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the alanine (A) at amino acid position 53 to be replaced by a threonine (T). 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	Benign	0.081
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.68
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.60	T;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.0010, 0.0020	.;B;B;.;.;B
Vest4		0.11, 0.12, 0.054
MutPred		0.18		Gain of phosphorylation at A53 (P = 0.0563);Gain of phosphorylation at A53 (P = 0.0563);Gain of phosphorylation at A53 (P = 0.0563);Gain of phosphorylation at A53 (P = 0.0563);Gain of phosphorylation at A53 (P = 0.0563);.;
MVP		0.59
MPC		0.012
ClinPred		0.16	T
GERP RS		-1.4
Varity_R		0.051
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762027896; hg19: chr19-45848956;