Genetic Variant MYO19:p.Lys830Lys (chr17-36498533-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001163735.2(MYO19):c.2490A>G(p.Lys830Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,910 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 35 hom. )

Consequence

MYO19
NM_001163735.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.23

Publications

1 publications found

Variant links:

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]

MYO19 links:

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]

ZNHIT3 Gene-Disease associations (from GenCC):

PEHO syndrome
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Mayer-Rokitansky-Kuster-Hauser syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ZNHIT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 17-36498533-T-C is Benign according to our data. Variant chr17-36498533-T-C is described in ClinVar as Benign. ClinVar VariationId is 785567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1983/152362) while in subpopulation AFR AF = 0.0449 (1866/41582). AF 95% confidence interval is 0.0432. There are 56 homozygotes in GnomAd4. There are 938 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163735.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO19	NM_001163735.2	MANE Select	c.2490A>G	p.Lys830Lys	synonymous	Exon 25 of 26	NP_001157207.1	Q96H55-1
MYO19	NM_025109.6		c.1890A>G	p.Lys630Lys	synonymous	Exon 21 of 22	NP_079385.2
ZNHIT3	NM_001281432.2		c.*767T>C		3_prime_UTR	Exon 5 of 5	NP_001268361.1	Q15649-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO19	ENST00000614623.5	TSL:2 MANE Select	c.2490A>G	p.Lys830Lys	synonymous	Exon 25 of 26	ENSP00000479518.1	Q96H55-1
MYO19	ENST00000610930.4	TSL:5	c.1890A>G	p.Lys630Lys	synonymous	Exon 21 of 22	ENSP00000478437.1	Q96H55-4
MYO19	ENST00000611622.4	TSL:1	n.3307A>G		non_coding_transcript_exon	Exon 12 of 13

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1983

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0450

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00368

AC:

916

AN:

248682

AF XY:

0.00285

show subpopulations

Gnomad AFR exome

AF:

0.0506

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000373

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.00147

AC:

2143

AN:

1460548

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

975

AN XY:

726280

show subpopulations

African (AFR)

AF:

0.0477

AC:

1596

AN:

33450

American (AMR)

AF:

0.00295

AC:

132

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.000104

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000194

AC:

215

AN:

1110904

Other (OTH)

AF:

0.00307

AC:

185

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

116

232

349

465

581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0130

AC:

1983

AN:

152362

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

938

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.0449

AC:

1866

AN:

41582

American (AMR)

AF:

0.00496

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68032

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0151

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.3

(source)

DANN

Benign

0.69

PhyloP100

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over