16-15703360-G-A

Position:

• chr16-15703360-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002474.3(MYH11):​c.*631C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 236,244 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (7 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-15703360-G-A is Benign according to our data. Variant chr16-15703360-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 887908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0062 (944/152264) while in subpopulation NFE AF= 0.0102 (693/68014). AF 95% confidence interval is 0.00956. There are 3 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.*772C>T		3_prime_UTR_variant	43/43	ENST00000452625.7
MYH11	NM_002474.3	c.*631C>T		3_prime_UTR_variant	41/41	ENST00000300036.6
NDE1	NM_017668.3	c.947+6500G>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.*631C>T		3_prime_UTR_variant	41/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.*772C>T		3_prime_UTR_variant	43/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.947+6500G>A		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00789 AC: 663 AN: 83980 Hom.: 7 Cov.: 0 AF XY: 0.00820 AC XY: 323 AN XY: 39372

Gnomad4 AFR exome AF: 0.000556

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.00582 AC XY: 433 AN XY: 74432

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00715 Hom.: 0

Bravo AF: 0.00625

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs112926446; hg19: chr16-15797217;