rs749181134

Variant names:

• chr16-15721604-T-G
• rs749181134
• NM_002474.3:c.4396A>C
• MYH11 p.Lys1466Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_002474.3(MYH11):c.4396A>C (p.Lys1466Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000041 (AC=6) in the gnomAD database across 1,461,894 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000194. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

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]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000194 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.4396A>C	p.Lys1466Gln	missense	Exon 32 of 41	NP_002465.1	A0A024QZJ4
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4417A>C	p.Lys1473Gln	missense	Exon 33 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-2587T>G		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.4396A>C	p.Lys1466Gln	missense	Exon 32 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4417A>C	p.Lys1473Gln	missense	Exon 33 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.4417A>C	p.Lys1473Gln	missense	Exon 33 of 42	ENSP00000379616.3	P35749-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251474	Cov:
GnomAD4 exome	AF: 0.00000410	AC:6	Hom:0	AN:1461894	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	100336	0.00000553	1	180986

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 4 (1)
-	1	-	Congenital aneurysm of ascending aorta (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.69
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.89	D
FuncVEP CTI	Benign	0.20
GPN-Star LLR	N/A	-9.1
GPN-Star score	N/A	9.1
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.18	T
Mutation Taster	N/A	89/11	polymorphism
MutationAssessor	Benign	0.99	L
PhyloP100	Uncertain	4.1
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.44
Sift	Benign	0.49	T
Sift4G	Benign	0.33	T
Varity_R	N/A	0.27
VESM-3B	Benign	-8.9

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749181134;

hg19: chr16-15815461;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar