16-15703447-C-T

Position:

• chr16-15703447-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002474.3(MYH11):​c.*544G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 239,950 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (60 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (4 hom.)
• Consequence: MYH11 NM_002474.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.932

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=-0.84).
• BP6: Variant 16-15703447-C-T is Benign according to our data. Variant chr16-15703447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 318077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_001040113.2	c.*685G>A		3_prime_UTR_variant	43/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_002474.3	c.*544G>A		3_prime_UTR_variant	41/41	ENST00000300036.6	NP_002465.1
NDE1	NM_017668.3	c.947+6587C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.*544G>A		3_prime_UTR_variant	41/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.*685G>A		3_prime_UTR_variant	43/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.947+6587C>T		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2422 AN: 152150 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00392 AC: 344 AN: 87682 Hom.: 4 Cov.: 0 AF XY: 0.00376 AC XY: 154 AN XY: 41000

Gnomad4 AFR exome AF: 0.0474

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000170

Gnomad4 SAS exome AF: 0.000583

Gnomad4 FIN exome AF: 0.00714

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00677

GnomAD4 genome AF: 0.0160 AC: 2429 AN: 152268 Hom.: 60 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74462

Gnomad4 AFR AF: 0.0520

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0108 Hom.: 4

Bravo AF: 0.0183

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

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 4 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aortic aneurysm, familial thoracic 4 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.33
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs116721094; hg19: chr16-15797304;