NM_002474.3:c.*420C>G

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: 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=-0.84).
• BP6: Variant 16-15703571-G-C is Benign according to our data. Variant chr16-15703571-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

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.*420C>G		3_prime_UTR	Exon 41 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.*561C>G		3_prime_UTR	Exon 43 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.947+6711G>C		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.*420C>G		3_prime_UTR	Exon 41 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.*561C>G		3_prime_UTR	Exon 43 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.*420C>G		3_prime_UTR	Exon 42 of 42	ENSP00000379616.3	P35749-2

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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;