rs372698538

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002474.3(MYH11):c.2653-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,812 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 2 hom. )

Consequence

MYH11
NM_002474.3 splice_region, intron

Scores

Splicing: ADA: 0.00006926

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.142

Publications

0 publications found

Variant links:

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]

MYH11 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
aortic aneurysm, familial thoracic 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
megacystis-microcolon-intestinal hypoperistalsis syndrome 2
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
megacystis-microcolon-intestinal hypoperistalsis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
visceral myopathy 2
Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MYH11 links:

ENSG00000263065 (HGNC:):

ENSG00000263065 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 16-15741676-G-A is Benign according to our data. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15741676-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 534164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000263 (4/152236) while in subpopulation SAS AF = 0.000621 (3/4834). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.2653-7C>T	splice_region_variant, intron_variant	Intron 21 of 40	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.2674-7C>T	splice_region_variant, intron_variant	Intron 22 of 42	ENST00000452625.7	NP_001035202.1	P35749-3
MYH11	NM_001040114.2 link	c.2674-7C>T	splice_region_variant, intron_variant	Intron 22 of 41		NP_001035203.1	P35749-2
MYH11	NM_022844.3 link	c.2653-7C>T	splice_region_variant, intron_variant	Intron 21 of 41		NP_074035.1	P35749-4A0A024QZJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 link	c.2653-7C>T		splice_region_variant, intron_variant	Intron 21 of 40	1	NM_002474.3	ENSP00000300036.5		P35749-1
MYH11	ENST00000452625.7 link	c.2674-7C>T		splice_region_variant, intron_variant	Intron 22 of 42	1	NM_001040113.2	ENSP00000407821.2		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251252

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000359

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Nov 05, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 4

Benign:1

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.11

(source)

DANN

Benign

0.41

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000069

dbscSNV1_RF

Benign

0.028

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over