rs2075512

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4953+63G>A		intron_variant	Intron 34 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4974+63G>A		intron_variant	Intron 35 of 42	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-4103C>T		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4953+63G>A		intron_variant	Intron 34 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4974+63G>A		intron_variant	Intron 35 of 42	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-4103C>T		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

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

Gnomad4 AFR exome AF: 0.849

Gnomad4 AMR exome AF: 0.667

Gnomad4 ASJ exome AF: 0.623

Gnomad4 EAS exome AF: 0.515

Gnomad4 SAS exome AF: 0.706

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.589

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

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.518

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.601

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.644

Alfa AF: 0.618 Hom.: 4147

Bravo AF: 0.664

Asia WGS AF: 0.605 AC: 2105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0020
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075512; hg19: chr16-15813945; COSMIC: COSV55556343; COSMIC: COSV55556343;