rs574893374

Variant names:

• chr16-15718443-G-A
• rs574893374
• NM_002474.3:c.5172-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.5172-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,555,058 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (11 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, intron
• Scores: Splicing: ADA: 0.0006565
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.280
• 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: 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=-0.68).
• BP6: Variant 16-15718443-G-A is Benign according to our data. Variant chr16-15718443-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000322 (49/152330) while in subpopulation SAS AF = 0.00993 (48/4834). AF 95% confidence interval is 0.0077. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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.5172-5C>T		splice_region intron	N/A	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5193-5C>T		splice_region intron	N/A	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-5748G>A		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.5172-5C>T		splice_region intron	N/A	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5193-5C>T		splice_region intron	N/A	ENSP00000407821.2	P35749-3
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-5748G>A		intron	N/A	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00159 AC: 267 AN: 167578 AF XY: 0.00207

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000629

GnomAD4 exome AF: 0.000595 AC: 835 AN: 1402728 Hom.: 11 Cov.: 31 AF XY: 0.000866 AC XY: 601 AN XY: 694316

African (AFR) AF: 0.00 AC: 0 AN: 32320

American (AMR) AF: 0.00 AC: 0 AN: 37858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37032

South Asian (SAS) AF: 0.00940 AC: 773 AN: 82226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 0.00000645 AC: 7 AN: 1085004

Other (OTH) AF: 0.000927 AC: 54 AN: 58260

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00993 AC: 48 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000471 Hom.: 0

Bravo AF: 0.0000567

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	MYH11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.4
DANN	Benign	0.85
PhyloP100		0.28
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.0080
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: rs574893374; hg19: chr16-15812300;