rs747642850

Positions:

• chr16-15708848-CAGAG-C
• chr16-15708848-CAGAG-CAG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_001040113.2(MYH11):​c.5808-11_5808-8del variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000424 in 1,609,690 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: MYH11 NM_001040113.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.42

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 16-15708848-CAGAG-C is Benign according to our data. Variant chr16-15708848-CAGAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 201040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15708848-CAGAG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000414 (63/152264) while in subpopulation AMR AF= 0.00118 (18/15286). AF 95% confidence interval is 0.000761. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.5808-11_5808-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000452625.7
MYH11	NM_002474.3	c.5787-4729_5787-4726del		intron_variant		ENST00000300036.6
NDE1	NM_017668.3	c.947+11994_947+11997del		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5787-4729_5787-4726del		intron_variant		1	NM_002474.3	P3
NDE1	ENST00000396354.6	c.947+11994_947+11997del		intron_variant		1	NM_017668.3	P1
MYH11	ENST00000452625.7	c.5808-11_5808-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000420 AC: 102 AN: 242886 Hom.: 0 AF XY: 0.000427 AC XY: 56 AN XY: 131050

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.000743

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.000240

Gnomad FIN exome AF: 0.0000948

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000425 AC: 620 AN: 1457426 Hom.: 0 AF XY: 0.000418 AC XY: 303 AN XY: 724386

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000591

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000377

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.000466

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74442

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2013	The variant is found in TAAD panel(s). -

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 20, 2023

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;