chr6-2688920-C-T

Position:

• chr6-2688920-C-T

Variant summary

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

The NM_001012418.5(MYLK4):​c.272G>A​(p.Arg91His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,854 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: 0.0000027 (0 hom.)
• Consequence: MYLK4 NM_001012418.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK4	NM_001012418.5	c.272G>A	p.Arg91His	missense_variant	4/13	ENST00000274643.9	NP_001012418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK4	ENST00000274643.9	c.272G>A	p.Arg91His	missense_variant	4/13	1	NM_001012418.5	ENSP00000274643.7
MYLK4	ENST00000698899.1	c.440G>A	p.Arg147His	missense_variant	4/13			ENSP00000514016.1
MYLK4	ENST00000647417.1	c.254G>A	p.Arg85His	missense_variant	3/12			ENSP00000494309.1
MYLK4	ENST00000698900.1	n.533G>A		non_coding_transcript_exon_variant	5/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 04, 2024

The c.272G>A (p.R91H) alteration is located in exon 4 (coding exon 3) of the MYLK4 gene. This alteration results from a G to A substitution at nucleotide position 272, causing the arginine (R) at amino acid position 91 to be replaced by a histidine (H). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.9	.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	.;D
Polyphen		1.0	.;D
Vest4		0.71
MutPred		0.43		.;Gain of ubiquitination at K96 (P = 0.0707);
MVP		0.75
MPC		0.75
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.42
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1312872346; hg19: chr6-2689154; COSMIC: COSV51151924;