rs587781062

Variant names:

• chr16-15721419-T-C
• rs143288748
• NM_002474.3:c.4578+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-15721419-T-C
• chrNT_187607.1-1379430-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.4578+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,614,072 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, intron
• Scores: Splicing: ADA: 0.004251
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 0.597
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-15721419-T-C is Benign according to our data. Variant chr16-15721419-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138346.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (212/152318) while in subpopulation NFE AF = 0.00235 (160/68032). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR,Unknown 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.4578+3A>G		splice_region intron	N/A	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4599+3A>G		splice_region intron	N/A	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-2772T>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.4578+3A>G		splice_region intron	N/A	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4599+3A>G		splice_region intron	N/A	ENSP00000407821.2	P35749-3
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-2772T>C		intron	N/A	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00134 AC: 338 AN: 251476 AF XY: 0.00138

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00218 AC: 3180 AN: 1461754 Hom.: 7 Cov.: 32 AF XY: 0.00213 AC XY: 1546 AN XY: 727182

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00125 AC: 56 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86250

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53404

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00261 AC: 2900 AN: 1111918

Other (OTH) AF: 0.00123 AC: 74 AN: 60382

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74480

African (AFR) AF: 0.000265 AC: 11 AN: 41580

American (AMR) AF: 0.00190 AC: 29 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00124

EpiCase AF: 0.00289

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	Aortic aneurysm, familial thoracic 4 (6)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.81
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0043
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs143288748; hg19: chr16-15815276;