Variant 6-2678371-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001012418.5(MYLK4):c.889C>A(p.Leu297Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYLK4
NM_001012418.5 missense, splice_region

Scores

Splicing: ADA: 0.9856

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

Variant links:

Genes affected

MYLK4 (HGNC:27972): (myosin light chain kinase family member 4) Predicted to enable myosin light chain kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MYLK4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYLK4	NM_001012418.5 linkuse as main transcript	c.889C>A	p.Leu297Ile	missense_variant, splice_region_variant	10/13	ENST00000274643.9
MYLK4	NM_001347872.2 linkuse as main transcript	c.1057C>A	p.Leu353Ile	missense_variant, splice_region_variant	10/13
MYLK4	XM_005249078.5 linkuse as main transcript	c.1132C>A	p.Leu378Ile	missense_variant, splice_region_variant	10/13
MYLK4	XM_006715082.4 linkuse as main transcript	c.871C>A	p.Leu291Ile	missense_variant, splice_region_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK4	ENST00000274643.9 linkuse as main transcript	c.889C>A	p.Leu297Ile	missense_variant, splice_region_variant	10/13	1	NM_001012418.5	A2	Q86YV6-1
MYLK4	ENST00000698899.1 linkuse as main transcript	c.1057C>A	p.Leu353Ile	missense_variant, splice_region_variant	10/13			A2
MYLK4	ENST00000647417.1 linkuse as main transcript	c.871C>A	p.Leu291Ile	missense_variant, splice_region_variant	9/12			P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2022

The c.889C>A (p.L297I) alteration is located in exon 10 (coding exon 9) of the MYLK4 gene. This alteration results from a C to A substitution at nucleotide position 889, causing the leucine (L) at amino acid position 297 to be replaced by an isoleucine (I). 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

0.16

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.9

.;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.029

.;D

Sift4G

Uncertain

0.023

.;D

Polyphen

0.99

.;D

Vest4

0.81

MutPred

0.82

.;Loss of catalytic residue at L297 (P = 0.0213);

MVP

0.48

MPC

0.71

ClinPred

0.97

GERP RS

5.1

Varity_R

0.65

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.83

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over