rs34839877

Variant names:

• chr16-15718452-G-A
• rs34839877
• NM_002474.3:c.5172-14C>T

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.5172-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,547,344 control chromosomes in the GnomAD database, including 1,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (150 hom., cov: 32)
  • Exomes 𝑓: 0.031 (951 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.227
• Publications: 1 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=-0.9).
• BP6: Variant 16-15718452-G-A is Benign according to our data. Variant chr16-15718452-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0867 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5172-14C>T		intron	N/A	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5193-14C>T		intron	N/A	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-5739G>A		intron	N/A	NP_060138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5172-14C>T		intron	N/A	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5193-14C>T		intron	N/A	ENSP00000407821.2
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-5739G>A		intron	N/A	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5637 AN: 152134 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0370 AC: 5797 AN: 156676 AF XY: 0.0421

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0130

Gnomad FIN exome AF: 0.0346

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0306 AC: 42672 AN: 1395092 Hom.: 951 Cov.: 31 AF XY: 0.0323 AC XY: 22288 AN XY: 689910

African (AFR) AF: 0.0542 AC: 1736 AN: 32012

American (AMR) AF: 0.0160 AC: 588 AN: 36750

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 683 AN: 25352

East Asian (EAS) AF: 0.00818 AC: 298 AN: 36420

South Asian (SAS) AF: 0.0844 AC: 6875 AN: 81444

European-Finnish (FIN) AF: 0.0310 AC: 1189 AN: 38350

Middle Eastern (MID) AF: 0.0321 AC: 151 AN: 4704

European-Non Finnish (NFE) AF: 0.0269 AC: 29154 AN: 1081998

Other (OTH) AF: 0.0344 AC: 1998 AN: 58062

GnomAD4 genome AF: 0.0373 AC: 5673 AN: 152252 Hom.: 150 Cov.: 32 AF XY: 0.0389 AC XY: 2894 AN XY: 74434

African (AFR) AF: 0.0517 AC: 2147 AN: 41536

American (AMR) AF: 0.0322 AC: 493 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.00832 AC: 43 AN: 5168

South Asian (SAS) AF: 0.0938 AC: 452 AN: 4818

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1927 AN: 68020

Other (OTH) AF: 0.0449 AC: 95 AN: 2116

Alfa AF: 0.0323 Hom.: 14

Bravo AF: 0.0355

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Aortic aneurysm, familial thoracic 4 (4)
-	-	4	not specified (4)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Familial aortopathy (1)
-	-	1	Lissencephaly 4 (1)
-	-	1	Lissencephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.6
DANN	Benign	0.56
PhyloP100		0.23
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: rs34839877; hg19: chr16-15812309; COSMIC: COSV107354264; COSMIC: COSV107354264;