Variant 20-36545063-CGCTGGGTGA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_006097.5(MYL9):c.184+2_184+10delTGAGCTGGG variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MYL9
NM_006097.5 splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

MYL9 (HGNC:15754): (myosin light chain 9) Myosin, a structural component of muscle, consists of two heavy chains and four light chains. The protein encoded by this gene is a myosin light chain that may regulate muscle contraction by modulating the ATPase activity of myosin heads. The encoded protein binds calcium and is activated by myosin light chain kinase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MYL9 links:

DLGAP4-AS1 (HGNC:51223): (DLGAP4 antisense RNA 1)

DLGAP4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.40462428 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 13, new splice context is: gggGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYL9	NM_006097.5 link	c.184+2_184+10delTGAGCTGGG	splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 3	ENST00000279022.7	NP_006088.2	P24844-1A0A384NY64
MYL9	NM_181526.3 link	c.184+2_184+10delTGAGCTGGG	splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 2		NP_852667.1	P24844-2
DLGAP4-AS1	NR_109939.1 link	n.467+26369_467+26377delTCACCCAGC	intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL9	ENST00000279022.7 link	c.180_184+4delGCTGGGTGA	p.Leu61AsnfsTer110	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 4	1	NM_006097.5	ENSP00000279022.2	P24844-1
MYL9	ENST00000346786.2 link	c.180_184+4delGCTGGGTGA	p.Leu61IlefsTer56	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 3	1		ENSP00000217313.2	P24844-2
DLGAP4-AS1	ENST00000439595.5 link	n.467+26369_467+26377delTCACCCAGC		intron_variant	Intron 2 of 4	1
DLGAP4-AS1	ENST00000425233.6 link	n.580-17148_580-17140delTCACCCAGC		intron_variant	Intron 2 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250924

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461478

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Megacystis-microcolon-intestinal hypoperistalsis syndrome 4

Pathogenic:1

Jun 16, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Visceral myopathy 1

Uncertain:1

Feb 26, 2020

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This intronic variant, NM_006097.4:c.184+2_184+10del, was identified in trans with a heterozygous deletion of exon 4 in an individual with a clinical diagnosis of MMIH syndrome: bilateral hydronephrosis, megacystis, congenital bilateral mydriasis, lack of urinary bladder peristalsis, and intestinal pseudo-obstruction. This intronic variant alters the highly conserved splice donor site for exon 2 of this transcript and is predicted by five splice site prediction tools queried to abolish canonical splice donor activity. This variant is expected to result in altered function of the MYL9 gene product as a result of aberrant splicing. This variant has been observed at a frequency of less than 0.01% (2/245706 alleles) across the entire Broad data set (individuals without severe childhood onset disease). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over