16-15708830-G-T

Variant names:

• chr16-15708830-G-T
• rs111588143
• NM_001040113.2:c.5819C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040113.2(MYH11):​c.5819C>A​(p.Pro1940Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,605,908 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1940A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: MYH11 NM_001040113.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 1.54
• Publications: 6 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]

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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hydranencephaly

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

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077909827).
• BP6: Variant 16-15708830-G-T is Benign according to our data. Variant chr16-15708830-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00331 (503/151838) while in subpopulation AFR AF = 0.00891 (369/41422). AF 95% confidence interval is 0.00816. There are 4 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040113.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5819C>A	p.Pro1940Gln	missense	Exon 42 of 43	NP_001035202.1	P35749-3
	MYH11	NM_002474.3	MANE Select	c.5787-4707C>A		intron	N/A	NP_002465.1	P35749-1
	NDE1	NM_017668.3	MANE Select	c.947+11970G>T		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5819C>A	p.Pro1940Gln	missense	Exon 42 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000576790.7	TSL:1	c.5798C>A	p.Pro1933Gln	missense	Exon 41 of 42	ENSP00000458731.1	P35749-4
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5787-4707C>A		intron	N/A	ENSP00000300036.5	P35749-1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 501 AN: 151720 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00889

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00133 AC: 311 AN: 233460 AF XY: 0.00117

Gnomad AFR exome AF: 0.00876

Gnomad AMR exome AF: 0.000771

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.000691

Gnomad FIN exome AF: 0.000290

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00147 AC: 2132 AN: 1454070 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 1021 AN XY: 722608

African (AFR) AF: 0.00788 AC: 263 AN: 33384

American (AMR) AF: 0.000891 AC: 39 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25906

East Asian (EAS) AF: 0.000961 AC: 38 AN: 39562

South Asian (SAS) AF: 0.000260 AC: 22 AN: 84706

European-Finnish (FIN) AF: 0.000415 AC: 22 AN: 53002

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5740

European-Non Finnish (NFE) AF: 0.00148 AC: 1643 AN: 1107842

Other (OTH) AF: 0.00161 AC: 97 AN: 60156

GnomAD4 genome AF: 0.00331 AC: 503 AN: 151838 Hom.: 4 Cov.: 33 AF XY: 0.00327 AC XY: 243 AN XY: 74236

African (AFR) AF: 0.00891 AC: 369 AN: 41422

American (AMR) AF: 0.00210 AC: 32 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4794

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00124 AC: 84 AN: 67904

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.00340

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00774 AC: 34

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00138 AC: 167

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	1	1	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.58	T
PhyloP100		1.5
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.43	T
Vest4		0.39
MVP		0.43
ClinPred		0.041	T
GERP RS		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111588143; hg19: chr16-15802687; COSMIC: COSV100257523; COSMIC: COSV100257523;