rs2075512

Variant names:

• chr16-15720088-C-T
• rs2075512
• NM_002474.3:c.4953+63G>A

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.4953+63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,608,058 control chromosomes in the GnomAD database, including 275,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33669 hom., cov: 30)
  • Exomes 𝑓: 0.57 (242108 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.00
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-15720088-C-T is Benign according to our data. Variant chr16-15720088-C-T is described in ClinVar as Benign. ClinVar VariationId is 672359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 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.4953+63G>A		intron	N/A	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4974+63G>A		intron	N/A	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-4103C>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.4953+63G>A		intron	N/A	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4974+63G>A		intron	N/A	ENSP00000407821.2	P35749-3
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-4103C>T		intron	N/A	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99253 AN: 151784 Hom.: 33615 Cov.: 30

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.643

GnomAD4 exome AF: 0.572 AC: 833606 AN: 1456156 Hom.: 242108 AF XY: 0.576 AC XY: 417525 AN XY: 724796

African (AFR) AF: 0.849 AC: 28340 AN: 33376

American (AMR) AF: 0.667 AC: 29793 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16271 AN: 26104

East Asian (EAS) AF: 0.515 AC: 20420 AN: 39672

South Asian (SAS) AF: 0.706 AC: 60861 AN: 86146

European-Finnish (FIN) AF: 0.588 AC: 31298 AN: 53186

Middle Eastern (MID) AF: 0.706 AC: 4064 AN: 5760

European-Non Finnish (NFE) AF: 0.548 AC: 607111 AN: 1106992

Other (OTH) AF: 0.589 AC: 35448 AN: 60220

GnomAD4 genome AF: 0.654 AC: 99370 AN: 151902 Hom.: 33669 Cov.: 30 AF XY: 0.657 AC XY: 48776 AN XY: 74220

African (AFR) AF: 0.839 AC: 34788 AN: 41454

American (AMR) AF: 0.652 AC: 9938 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2187 AN: 3472

East Asian (EAS) AF: 0.518 AC: 2668 AN: 5148

South Asian (SAS) AF: 0.700 AC: 3367 AN: 4812

European-Finnish (FIN) AF: 0.601 AC: 6334 AN: 10534

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37897 AN: 67924

Other (OTH) AF: 0.644 AC: 1357 AN: 2106

Alfa AF: 0.618 Hom.: 4147

Bravo AF: 0.664

Asia WGS AF: 0.605 AC: 2105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0020
DANN	Benign	0.42
PhyloP100		-4.0
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: rs2075512; hg19: chr16-15813945; COSMIC: COSV55556343; COSMIC: COSV55556343;