rs12932063

Variant names:

• chr16-15703571-G-C
• rs12932063
• NM_002474.3:c.*420C>G

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.*420C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 340,898 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (153 hom., cov: 32)
  • Exomes 𝑓: 0.030 (149 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0680
• Publications: 2 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: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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=-0.84).
• BP6: Variant 16-15703571-G-C is Benign according to our data. Variant chr16-15703571-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 318081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.*420C>G		3_prime_UTR_variant	Exon 41 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.*561C>G		3_prime_UTR_variant	Exon 43 of 43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.947+6711G>C		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.*420C>G		3_prime_UTR_variant	Exon 41 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.*561C>G		3_prime_UTR_variant	Exon 43 of 43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.947+6711G>C		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5750 AN: 152066 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0301 AC: 5676 AN: 188714 Hom.: 149 Cov.: 0 AF XY: 0.0334 AC XY: 3181 AN XY: 95122

African (AFR) AF: 0.0530 AC: 390 AN: 7362

American (AMR) AF: 0.0188 AC: 134 AN: 7128

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 177 AN: 7452

East Asian (EAS) AF: 0.00731 AC: 124 AN: 16952

South Asian (SAS) AF: 0.0718 AC: 1332 AN: 18544

European-Finnish (FIN) AF: 0.0291 AC: 119 AN: 4096

Middle Eastern (MID) AF: 0.0253 AC: 45 AN: 1780

European-Non Finnish (NFE) AF: 0.0264 AC: 2986 AN: 113306

Other (OTH) AF: 0.0305 AC: 369 AN: 12094

GnomAD4 genome AF: 0.0380 AC: 5781 AN: 152184 Hom.: 153 Cov.: 32 AF XY: 0.0395 AC XY: 2940 AN XY: 74382

African (AFR) AF: 0.0544 AC: 2258 AN: 41518

American (AMR) AF: 0.0327 AC: 500 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3468

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5188

South Asian (SAS) AF: 0.0930 AC: 449 AN: 4830

European-Finnish (FIN) AF: 0.0312 AC: 330 AN: 10590

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1923 AN: 68004

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0343 Hom.: 8

Bravo AF: 0.0363

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lissencephaly 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.84
CADD	Benign	0.85
DANN	Benign	0.44
PhyloP100		-0.068
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: rs12932063; hg19: chr16-15797428;