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rs9622375

chr22-36309402-G-Achr22-36309402-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002473.6(MYH9):c.1729-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,611,984 control chromosomes in the GnomAD database, including 33 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 0.0068 ( 18 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 15 hom. )

Consequence

MYH9
NM_002473.6 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00002602
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.44
Variant links:
Genes affected
MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 22-36309402-G-A is Benign according to our data. Variant chr22-36309402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36309402-G-A is described in Lovd as [Likely_benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00677 (1032/152328) while in subpopulation AFR AF= 0.0222 (922/41568). AF 95% confidence interval is 0.021. There are 18 homozygotes in gnomad4. There are 466 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1033 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH9NM_002473.6 linkuse as main transcriptc.1729-6C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000216181.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH9ENST00000216181.11 linkuse as main transcriptc.1729-6C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_002473.6 P1P35579-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00679
AC:
1033
AN:
152210
Hom.:
18
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0223
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
Gnomad ASJ
AF:
0.00922
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00670
GnomAD3 exomes
AF:
0.00244
AC:
612
AN:
251170
Hom.:
4
AF XY:
0.00204
AC XY:
277
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.0232
Gnomad AMR exome
AF:
0.00203
Gnomad ASJ exome
AF:
0.0114
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000326
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00105
AC:
1534
AN:
1459656
Hom.:
15
Cov.:
31
AF XY:
0.000973
AC XY:
707
AN XY:
726256
show subpopulations
Gnomad4 AFR exome
AF:
0.0228
Gnomad4 AMR exome
AF:
0.00235
Gnomad4 ASJ exome
AF:
0.00980
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000178
Gnomad4 OTH exome
AF:
0.00318
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00677
AC:
1032
AN:
152328
Hom.:
18
Cov.:
33
AF XY:
0.00626
AC XY:
466
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.0222
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00922
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00425
Hom.:
1
Bravo
AF:
0.00794
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.000600
EpiControl
AF:
0.000474

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 20121729-6C>T in Intron 14 of MYH9: This variant is not expected to have clinical si gnificance because it has been identified in 1.7% (65/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs9622375). -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 15, 2017- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Autosomal dominant nonsyndromic hearing loss 17 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Kidney disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 01, 2020- -
Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 28, 2021- -
MYH9-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
-0.87
Cadd
Benign
7.6
Dann
Benign
0.65
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000026
dbscSNV1_RF
Benign
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs9622375; hg19: chr22-36705447; API