rs200737737

Positions:

• chr16-15724941-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.3910A>C​(p.Ile1304Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000172 in 1,614,140 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (5 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.14

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.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.038374722).
• BP6: Variant 16-15724941-T-G is Benign according to our data. Variant chr16-15724941-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000788 (12/152284) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3910A>C	p.Ile1304Leu	missense_variant	29/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3931A>C	p.Ile1311Leu	missense_variant	30/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.*690T>G		3_prime_UTR_variant	9/9	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3910A>C	p.Ile1304Leu	missense_variant	29/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.3931A>C	p.Ile1311Leu	missense_variant	30/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.*690T>G		3_prime_UTR_variant	9/9	1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251392 Hom.: 2 AF XY: 0.000397 AC XY: 54 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461856 Hom.: 5 Cov.: 34 AF XY: 0.000256 AC XY: 186 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2017	The p.I1304L variant (also known as c.3910A>C), located in coding exon 28 of the MYH11 gene, results from an A to C substitution at nucleotide position 3910. The isoleucine at codon 1304 is replaced by leucine, an amino acid with highly similar properties, and is located in the coiled coil domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2018	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	.;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.62	N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.76	T;T;.;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.010	.;.;.;B
Vest4		0.45
MVP		0.61
MPC		0.71
ClinPred		0.043	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.10

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: rs200737737; hg19: chr16-15818798;