NM_002474.3:c.5172-13G>T

Variant names:

• chr16-15718451-C-A
• rs373378619
• NM_002474.3:c.5172-13G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002474.3(MYH11):​c.5172-13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5172-13G>T		intron_variant	Intron 36 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5193-13G>T		intron_variant	Intron 37 of 42	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-5740C>A		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.5172-13G>T		intron_variant	Intron 36 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5193-13G>T		intron_variant	Intron 37 of 42	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-5740C>A		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397216 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691144

African (AFR) AF: 0.00 AC: 0 AN: 32096

American (AMR) AF: 0.00 AC: 0 AN: 37060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25362

East Asian (EAS) AF: 0.00 AC: 0 AN: 36590

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082864

Other (OTH) AF: 0.00 AC: 0 AN: 58102

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.66
PhyloP100		0.68

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: rs373378619; hg19: chr16-15812308;