NM_002474.3:c.4681G>A

Variant names:

• chr16-15720949-C-T
• rs138863103
• NM_002474.3:c.4681G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_002474.3(MYH11):​c.4681G>A​(p.Ala1561Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 7.91
• Publications: 7 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 16-15720949-C-T is Benign according to our data. Variant chr16-15720949-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263877.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000711 (104/1461864) while in subpopulation AMR AF = 0.000313 (14/44722). AF 95% confidence interval is 0.000189. There are 0 homozygotes in GnomAdExome4. There are 50 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4681G>A	p.Ala1561Thr	missense	Exon 33 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4702G>A	p.Ala1568Thr	missense	Exon 34 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-3242C>T		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.4681G>A	p.Ala1561Thr	missense	Exon 33 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4702G>A	p.Ala1568Thr	missense	Exon 34 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.4702G>A	p.Ala1568Thr	missense	Exon 34 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251470 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 727240

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112012

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152040 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.000131 AC: 2 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.72
Sift	Benign	0.044	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.72
MPC		0.70
ClinPred		0.57	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.22
Mutation Taster		=19/81	disease causing

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: rs138863103; hg19: chr16-15814806; COSMIC: COSV55542217; COSMIC: COSV55542217;