16-15721421-C-G

Variant names:

• chr16-15721421-C-G
• rs397514037
• NM_002474.3:c.4578+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_002474.3(MYH11):​c.4578+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03598581 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of -30, new splice context is: ctgGTcagc. Cryptic site results in inframe 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
• PP5: Variant 16-15721421-C-G is Pathogenic according to our data. Variant chr16-15721421-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 581749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4578+1G>C		splice_donor_variant, intron_variant	Intron 32 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4599+1G>C		splice_donor_variant, intron_variant	Intron 33 of 42	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-2770C>G		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4578+1G>C		splice_donor_variant, intron_variant	Intron 32 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4599+1G>C		splice_donor_variant, intron_variant	Intron 33 of 42	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-2770C>G		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jul 02, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4578+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 31 of the MYH11 gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been detected in two individuals with thoracic aortic aneurysm and dissection (TAAD) (Ambry internal data; Invitae personal communication). Additional canonical variants at this splice site (also described as IVS32+1 and c.4599+1), including c.4578+1G>T, c.4578+1G>A, and c.4578delG, have been reported in individuals and families with TAAD and/or patent ductus arteriosus (PDA); RNA studies for variants c.4578+1G>T and c.4578+1delG showed splicing impact leads to in-frame loss of the coding exon (Zhu L et al. Nat. Genet., 2006 Mar;38:343-9; Renard M et al. Int. J. Cardiol., 2013 May;165:314-21; LaHaye S et al. Circ Cardiovasc Genet, 2016 Aug;9:320-9; Yang H et al. Sci Rep, 2016 09;6:33002). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Aortic aneurysm, familial thoracic 4 Pathogenic:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 33 of the MYH11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH11 cause disease. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with thoracic aortic aneurysm and dissection and/or patent ductus arteriosus (PMID: 16444274, 21937134, 27418595, 27611364; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 581749). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 31
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514037; hg19: chr16-15815278; COSMIC: COSV55570385; COSMIC: COSV55570385;