16-15720860-C-T

Variant names:

• chr16-15720860-C-T
• rs11648119
• NM_002474.3:c.4770G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002474.3(MYH11):​c.4770G>A​(p.Lys1590Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,842 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 31)
  • Exomes 𝑓: 0.018 (334 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.80
• Publications: 8 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: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-15720860-C-T is Benign according to our data. Variant chr16-15720860-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1974/152260) while in subpopulation NFE AF = 0.0211 (1433/68018). AF 95% confidence interval is 0.0202. There are 23 homozygotes in GnomAd4. There are 897 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.4770G>A	p.Lys1590Lys	synonymous	Exon 33 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4791G>A	p.Lys1597Lys	synonymous	Exon 34 of 43	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-3331C>T		intron	N/A	NP_060138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.4770G>A	p.Lys1590Lys	synonymous	Exon 33 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4791G>A	p.Lys1597Lys	synonymous	Exon 34 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.4791G>A	p.Lys1597Lys	synonymous	Exon 34 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1975 AN: 152142 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0136 AC: 3424 AN: 251274 AF XY: 0.0137

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0184 AC: 26867 AN: 1461582 Hom.: 334 Cov.: 32 AF XY: 0.0179 AC XY: 13025 AN XY: 727092

African (AFR) AF: 0.00281 AC: 94 AN: 33474

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 158 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00475 AC: 410 AN: 86246

European-Finnish (FIN) AF: 0.0276 AC: 1472 AN: 53368

Middle Eastern (MID) AF: 0.00162 AC: 9 AN: 5564

European-Non Finnish (NFE) AF: 0.0214 AC: 23760 AN: 1112006

Other (OTH) AF: 0.0128 AC: 773 AN: 60364

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 152260 Hom.: 23 Cov.: 31 AF XY: 0.0120 AC XY: 897 AN XY: 74452

African (AFR) AF: 0.00409 AC: 170 AN: 41562

American (AMR) AF: 0.00543 AC: 83 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1433 AN: 68018

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.0174 Hom.: 13

Bravo AF: 0.0109

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0168

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	2	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	not provided (2)
-	-	1	Familial aortopathy (1)
-	-	1	Lissencephaly 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.1
DANN	Benign	0.69
PhyloP100		2.8
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11648119; hg19: chr16-15814717; COSMIC: COSV55551003;