rs113667224

Variant names:

• chr16-15704110-T-A
• rs113667224
• NM_002474.3:c.5800A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-15704110-T-A
• chr16-15704110-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.5800A>T​(p.Thr1934Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,030 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -0.451
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005936742).
• BP6: Variant 16-15704110-T-A is Benign according to our data. Variant chr16-15704110-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201044.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00159 (242/152212) while in subpopulation NFE AF = 0.00291 (198/68020). AF 95% confidence interval is 0.00258. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5800A>T	p.Thr1934Ser	missense	Exon 41 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.*22A>T		3_prime_UTR	Exon 43 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.947+7250T>A		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.5800A>T	p.Thr1934Ser	missense	Exon 41 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000396324.7	TSL:1	c.5821A>T	p.Thr1941Ser	missense	Exon 42 of 42	ENSP00000379616.3	P35749-2
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.*22A>T		3_prime_UTR	Exon 43 of 43	ENSP00000407821.2	P35749-3

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00136 AC: 342 AN: 251458 AF XY: 0.00129

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00252 AC: 3678 AN: 1461818 Hom.: 5 Cov.: 31 AF XY: 0.00243 AC XY: 1769 AN XY: 727214

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00319 AC: 3542 AN: 1111972

Other (OTH) AF: 0.00131 AC: 79 AN: 60386

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74422

African (AFR) AF: 0.000578 AC: 24 AN: 41538

American (AMR) AF: 0.000786 AC: 12 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00170

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00124 AC: 151

EpiCase AF: 0.00349

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Aortic aneurysm, familial thoracic 4 (4)
-	-	4	not provided (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	1	Aortic aneurysm, familial thoracic 6 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.45
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.25
Sift	Benign	0.35	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.14		Gain of glycosylation at P1938 (P = 0.2403)
MVP		0.53
MPC		0.16
ClinPred		0.0054	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.25
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs113667224; hg19: chr16-15797967;