16-15708848-CAGAG-CAG

Position:

• chr16-15708848-CAGAG-CAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001040113.2(MYH11):​c.5808-9_5808-8del variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000116 in 1,609,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYH11 NM_001040113.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.93

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 16-15708848-CAG-C is Benign according to our data. Variant chr16-15708848-CAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465752.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000113 (165/1457436) while in subpopulation SAS AF= 0.000541 (46/84972). AF 95% confidence interval is 0.000417. There are 0 homozygotes in gnomad4_exome. There are 96 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.5808-9_5808-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000452625.7
MYH11	NM_002474.3	c.5787-4727_5787-4726del		intron_variant		ENST00000300036.6
NDE1	NM_017668.3	c.947+11996_947+11997del		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5787-4727_5787-4726del		intron_variant		1	NM_002474.3	P3
NDE1	ENST00000396354.6	c.947+11996_947+11997del		intron_variant		1	NM_017668.3	P1
MYH11	ENST00000452625.7	c.5808-9_5808-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000214 AC: 52 AN: 242886 Hom.: 0 AF XY: 0.000168 AC XY: 22 AN XY: 131050

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000891

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.000776

Gnomad SAS exome AF: 0.000480

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1457436 Hom.: 0 AF XY: 0.000133 AC XY: 96 AN XY: 724390

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000909

Gnomad4 ASJ exome AF: 0.000501

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000541

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74314

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MYH11: BP4 -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 05, 2020	- -

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs747642850; hg19: chr16-15802705;