17-36498271-G-T

Variant names:

• chr17-36498271-G-T
• rs1270488334
• NM_001163735.2:c.2752C>A

Variant summary

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

The NM_001163735.2(MYO19):​c.2752C>A​(p.Pro918Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO19 NM_001163735.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

Genes affected

MYO19 (HGNC:26234): (myosin XIX) Enables actin binding activity. Involved in regulation of cytokinesis and regulation of mitochondrial fission. Acts upstream of or within mitochondrion migration along actin filament. Located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNHIT3 (HGNC:12309): (zinc finger HIT-type containing 3) Predicted to enable thyroid hormone receptor binding activity. Predicted to be involved in box C/D snoRNP assembly; maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA); and snoRNA localization. Located in cytoplasm and nucleus. Implicated in PEHO syndrome. [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 rank	MANE	Protein	UniProt
MYO19	NM_001163735.2	c.2752C>A	p.Pro918Thr	missense_variant	Exon 25 of 26	ENST00000614623.5	NP_001157207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO19	ENST00000614623.5	c.2752C>A	p.Pro918Thr	missense_variant	Exon 25 of 26	2	NM_001163735.2	ENSP00000479518.1
MYO19	ENST00000610930.4	c.2152C>A	p.Pro718Thr	missense_variant	Exon 21 of 22	5		ENSP00000478437.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245626 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133482

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: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458086 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724882

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: 0.00000180

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

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2752C>A (p.P918T) alteration is located in exon 25 (coding exon 23) of the MYO19 gene. This alteration results from a C to A substitution at nucleotide position 2752, causing the proline (P) at amino acid position 918 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.34		Gain of MoRF binding (P = 0.0489);.;
MVP		0.47
ClinPred		0.97	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1270488334; hg19: chr17-34854115;