rs202120792

Variant names:

• chr16-15715088-C-T
• rs202120792
• NM_002474.3:c.5614-7G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002474.3(MYH11):​c.5614-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,606,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002497
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -2.88
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-15715088-C-T is Benign according to our data. Variant chr16-15715088-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318092.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000864 (13/150462) while in subpopulation SAS AF = 0.00085 (4/4704). AF 95% confidence interval is 0.00029. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 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.5614-7G>A		splice_region intron	N/A	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5635-7G>A		splice_region intron	N/A	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-9103C>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.5614-7G>A		splice_region intron	N/A	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5635-7G>A		splice_region intron	N/A	ENSP00000407821.2	P35749-3
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-9103C>T		intron	N/A	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes AF: 0.0000865 AC: 13 AN: 150340 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000220 AC: 55 AN: 249772 AF XY: 0.000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000973

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1455576 Hom.: 1 Cov.: 32 AF XY: 0.000166 AC XY: 120 AN XY: 724114

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.000426 AC: 19 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.000789 AC: 68 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50294

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5746

European-Non Finnish (NFE) AF: 0.0000712 AC: 79 AN: 1109662

Other (OTH) AF: 0.000200 AC: 12 AN: 60104

GnomAD4 genome AF: 0.0000864 AC: 13 AN: 150462 Hom.: 0 Cov.: 32 AF XY: 0.0000953 AC XY: 7 AN XY: 73476

African (AFR) AF: 0.00 AC: 0 AN: 40988

American (AMR) AF: 0.000264 AC: 4 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5050

South Asian (SAS) AF: 0.000850 AC: 4 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67716

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.044
DANN	Benign	0.64
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0060
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: rs202120792; hg19: chr16-15808945;