17-29074903-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_078471.4(MYO18A):c.6032A>T(p.Tyr2011Phe) 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 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 1.73

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYO18A
• BP4: Computational evidence support a benign effect (MetaRNN=0.07525796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO18A	NM_078471.4	c.6032A>T	p.Tyr2011Phe	missense_variant	42/42	ENST00000527372.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO18A	ENST00000527372.7	c.6032A>T	p.Tyr2011Phe	missense_variant	42/42	1	NM_078471.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249070 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 20, 2023

The c.6032A>T (p.Y2011F) alteration is located in exon 42 (coding exon 41) of the MYO18A gene. This alteration results from a A to T substitution at nucleotide position 6032, causing the tyrosine (Y) at amino acid position 2011 to be replaced by a phenylalanine (F). 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	0.087
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Benign	0.93
DEOGEN2	Benign	0.029	T;.;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.69	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.78	N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;T;T;.
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.18
MutPred		0.25		Loss of catalytic residue at Y2011 (P = 0.0205);.;.;.;
MVP		0.47
MPC		0.24
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.079
gMVP		0.14

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: rs1167874438; hg19: chr17-27401921;