16-15724985-A-G

Variant names:

• chr16-15724985-A-G
• rs16967510
• NM_002474.3:c.3866T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.3866T>C​(p.Val1289Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,613,508 control chromosomes in the GnomAD database, including 3,024 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1289L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (164 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2860 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 7.34
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034478605).
• BP6: Variant 16-15724985-A-G is Benign according to our data. Variant chr16-15724985-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.3866T>C	p.Val1289Ala	missense	Exon 29 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.3887T>C	p.Val1296Ala	missense	Exon 30 of 43	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.*734A>G		3_prime_UTR	Exon 9 of 9	NP_060138.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.3866T>C	p.Val1289Ala	missense	Exon 29 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.3887T>C	p.Val1296Ala	missense	Exon 30 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.3887T>C	p.Val1296Ala	missense	Exon 30 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6113 AN: 152054 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0665

Gnomad OTH AF: 0.0403

GnomAD2 exomes AF: 0.0396 AC: 9944 AN: 251062 AF XY: 0.0411

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0581 AC: 84925 AN: 1461336 Hom.: 2860 Cov.: 34 AF XY: 0.0575 AC XY: 41802 AN XY: 727002

African (AFR) AF: 0.00923 AC: 309 AN: 33478

American (AMR) AF: 0.0245 AC: 1096 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0626 AC: 1636 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0277 AC: 2386 AN: 86240

European-Finnish (FIN) AF: 0.0183 AC: 974 AN: 53240

Middle Eastern (MID) AF: 0.0513 AC: 296 AN: 5766

European-Non Finnish (NFE) AF: 0.0672 AC: 74737 AN: 1111684

Other (OTH) AF: 0.0577 AC: 3485 AN: 60380

GnomAD4 genome AF: 0.0402 AC: 6112 AN: 152172 Hom.: 164 Cov.: 32 AF XY: 0.0364 AC XY: 2710 AN XY: 74398

African (AFR) AF: 0.0114 AC: 475 AN: 41536

American (AMR) AF: 0.0347 AC: 530 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0235 AC: 113 AN: 4816

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10602

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0665 AC: 4521 AN: 67980

Other (OTH) AF: 0.0399 AC: 84 AN: 2106

Alfa AF: 0.0567 Hom.: 583

Bravo AF: 0.0407

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0605 AC: 233

ESP6500AA AF: 0.0137 AC: 60

ESP6500EA AF: 0.0651 AC: 560

ExAC AF: 0.0388 AC: 4711

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0587

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Aortic aneurysm, familial thoracic 4 (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly 4 (1)
-	-	1	Lissencephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.28	N
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.16	T
Sift4G	Benign	0.56	T
Polyphen		0.069	B
Vest4		0.30
MPC		0.28
ClinPred		0.028	T
GERP RS		5.2
Varity_R		0.094
gMVP		0.22
Mutation Taster		=100/0	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: rs16967510; hg19: chr16-15818842; COSMIC: COSV55553257; COSMIC: COSV55553257;