chr17-29074865-G-A

Position:

• chr17-29074865-G-A

Variant summary

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

The NM_078471.4(MYO18A):​c.6070C>T​(p.His2024Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO18A NM_078471.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

Genes affected

MYO18A (HGNC:31104): (myosin XVIIIA) The protein encoded by this gene can bind GOLPH3, linking the Golgi to the cytoskeleton and influencing Golgi membrane trafficking. The encoded protein is also part of a complex that assembles lamellar actomyosin bundles and may be required for cell migration. [provided by RefSeq, Oct 2016]

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=0.13637605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO18A	NM_078471.4	c.6070C>T	p.His2024Tyr	missense_variant	42/42	ENST00000527372.7	NP_510880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO18A	ENST00000527372.7	c.6070C>T	p.His2024Tyr	missense_variant	42/42	1	NM_078471.4	ENSP00000437073	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

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

Mar 28, 2024

The c.6070C>T (p.H2024Y) alteration is located in exon 42 (coding exon 41) of the MYO18A gene. This alteration results from a C to T substitution at nucleotide position 6070, causing the histidine (H) at amino acid position 2024 to be replaced by a tyrosine (Y). 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	0.072
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.052
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	0.94	N;N;N;N;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.77	N;N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.020	D;T;T;.
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.090	B;B;B;.
Vest4		0.27
MutPred		0.18		Gain of phosphorylation at H2024 (P = 2e-04);.;.;.;
MVP		0.56
MPC		0.31
ClinPred		0.66	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.29

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: rs1278539085; hg19: chr17-27401883;