rs117099942

Positions:

• chr19-17200417-G-A
• chr19-17200417-G-T

Variant summary

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

The NM_004145.4(MYO9B):​c.4363G>A​(p.Gly1455Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,578,960 control chromosomes in the GnomAD database, including 1,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (81 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1106 hom.)
• Consequence: MYO9B NM_004145.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.721

Genes affected

MYO9B (HGNC:7609): (myosin IXB) This gene encodes a member of the myosin family of actin-based molecular motor heavy chain proteins. The protein represents an unconventional myosin; it should not be confused with the conventional non-muscle myosin-9 (MYH9). The protein has four IQ motifs located in the neck domain that bind calmodulin, which serves as a light chain. The protein complex has a single-headed structure and exhibits processive movement on actin filaments toward the minus-end. The protein also has rho-GTPase activity. Polymorphisms in this gene are associated with celiac disease and ulcerative colitis susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018480718).
• BP6: Variant 19-17200417-G-A is Benign according to our data. Variant chr19-17200417-G-A is described in ClinVar as [Benign]. Clinvar id is 403217.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-17200417-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0277 (4216/152304) while in subpopulation NFE AF= 0.0438 (2981/68018). AF 95% confidence interval is 0.0425. There are 81 homozygotes in gnomad4. There are 1971 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO9B	NM_004145.4	c.4363G>A	p.Gly1455Ser	missense_variant	25/40	ENST00000682292.1
MYO9B	NM_001130065.2	c.4363G>A	p.Gly1455Ser	missense_variant	25/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO9B	ENST00000682292.1	c.4363G>A	p.Gly1455Ser	missense_variant	25/40		NM_004145.4	A2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4217 AN: 152186 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0482

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0297 AC: 5676 AN: 191160 Hom.: 110 AF XY: 0.0298 AC XY: 3061 AN XY: 102738

Gnomad AFR exome AF: 0.00682

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.0000732

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0312

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0377 AC: 53762 AN: 1426656 Hom.: 1106 Cov.: 31 AF XY: 0.0369 AC XY: 26111 AN XY: 706718

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.0000786

Gnomad4 SAS exome AF: 0.00927

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0277 AC: 4216 AN: 152304 Hom.: 81 Cov.: 32 AF XY: 0.0265 AC XY: 1971 AN XY: 74474

Gnomad4 AFR AF: 0.00700

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0482

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00662

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0438

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0395 Hom.: 179

Bravo AF: 0.0263

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0389 AC: 150

ESP6500AA AF: 0.00713 AC: 29

ESP6500EA AF: 0.0397 AC: 332

ExAC AF: 0.0244 AC: 2915

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.38
DEOGEN2	Benign	0.014	.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.61	.;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	.;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.76	.;.;T;.
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.082
MPC		0.32
ClinPred		0.000055	T
GERP RS		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.41

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: rs117099942; hg19: chr19-17311226; COSMIC: COSV68278934; COSMIC: COSV68278934;