rs112377790

Variant names:

• chr16-15724368-G-A
• rs112377790
• NM_002474.3:c.4158C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-15724368-G-A
• chr16-15724368-G-C

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.4158C>T​(p.Thr1386Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,090 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.582
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-15724368-G-A is Benign according to our data. Variant chr16-15724368-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.582 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00797 (1214/152244) while in subpopulation NFE AF = 0.0123 (839/68006). AF 95% confidence interval is 0.0116. There are 7 homozygotes in GnomAd4. There are 545 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.4158C>T	p.Thr1386Thr	synonymous	Exon 31 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4179C>T	p.Thr1393Thr	synonymous	Exon 32 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.*117G>A		3_prime_UTR	Exon 9 of 9	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.4158C>T	p.Thr1386Thr	synonymous	Exon 31 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4179C>T	p.Thr1393Thr	synonymous	Exon 32 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.4179C>T	p.Thr1393Thr	synonymous	Exon 32 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152126 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00857

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00884 AC: 2220 AN: 251118 AF XY: 0.00900

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00720

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00957

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0113 AC: 16476 AN: 1461846 Hom.: 124 Cov.: 72 AF XY: 0.0110 AC XY: 8000 AN XY: 727228

African (AFR) AF: 0.00185 AC: 62 AN: 33478

American (AMR) AF: 0.00816 AC: 365 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 369 AN: 26136

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.00250 AC: 216 AN: 86258

European-Finnish (FIN) AF: 0.00934 AC: 499 AN: 53398

Middle Eastern (MID) AF: 0.00957 AC: 55 AN: 5750

European-Non Finnish (NFE) AF: 0.0129 AC: 14300 AN: 1112008

Other (OTH) AF: 0.00982 AC: 593 AN: 60394

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152244 Hom.: 7 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74442

African (AFR) AF: 0.00224 AC: 93 AN: 41548

American (AMR) AF: 0.00765 AC: 117 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00857 AC: 91 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 839 AN: 68006

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00800 Hom.: 3

Bravo AF: 0.00789

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.0
DANN	Benign	0.82
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

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: rs112377790; hg19: chr16-15818225;