chr16-15703925-GTTTTT-G

Position:

• chr16-15703925-GTTTTT-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.*61_*65del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,606,394 control chromosomes in the GnomAD database, including 171 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (161 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.27

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 16-15703925-GTTTTT-G is Benign according to our data. Variant chr16-15703925-GTTTTT-G is described in ClinVar as [Likely_benign]. Clinvar id is 318085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00895 (1359/151808) while in subpopulation NFE AF= 0.0128 (867/67956). AF 95% confidence interval is 0.0121. There are 10 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.*202_*206del		3_prime_UTR_variant	43/43	ENST00000452625.7
MYH11	NM_002474.3	c.*61_*65del		3_prime_UTR_variant	41/41	ENST00000300036.6
NDE1	NM_017668.3	c.947+7069_947+7073del		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.*61_*65del		3_prime_UTR_variant	41/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.*202_*206del		3_prime_UTR_variant	43/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.947+7069_947+7073del		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1361 AN: 151690 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00283

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00969 AC: 2420 AN: 249778 Hom.: 28 AF XY: 0.00979 AC XY: 1323 AN XY: 135118

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00983

GnomAD4 exome AF: 0.0121 AC: 17610 AN: 1454586 Hom.: 161 AF XY: 0.0118 AC XY: 8553 AN XY: 723982

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00895 AC: 1359 AN: 151808 Hom.: 10 Cov.: 32 AF XY: 0.00970 AC XY: 720 AN XY: 74212

Gnomad4 AFR AF: 0.00196

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00293

Gnomad4 FIN AF: 0.0320

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00601 Hom.: 3

Bravo AF: 0.00662

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MYH11: BS1, BS2; NDE1: BS1, BS2 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lissencephaly, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5815842; hg19: chr16-15797782;