chr19-17101884-G-A

Position:

• chr19-17101884-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004145.4(MYO9B):​c.167G>A​(p.Arg56Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,414 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: MYO9B NM_004145.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.124

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYO9B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036690235).
• BP6: Variant 19-17101884-G-A is Benign according to our data. Variant chr19-17101884-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 781444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1631/152280) while in subpopulation AFR AF= 0.0376 (1562/41546). AF 95% confidence interval is 0.036. There are 32 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO9B	NM_004145.4	c.167G>A	p.Arg56Gln	missense_variant	2/40	ENST00000682292.1
MYO9B	NM_001130065.2	c.167G>A	p.Arg56Gln	missense_variant	2/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO9B	ENST00000682292.1	c.167G>A	p.Arg56Gln	missense_variant	2/40		NM_004145.4	A2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1628 AN: 152162 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00248 AC: 615 AN: 247610 Hom.: 4 AF XY: 0.00199 AC XY: 268 AN XY: 134640

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00111 AC: 1621 AN: 1461134 Hom.: 24 Cov.: 31 AF XY: 0.000973 AC XY: 707 AN XY: 726868

Gnomad4 AFR exome AF: 0.0396

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 152280 Hom.: 32 Cov.: 32 AF XY: 0.00998 AC XY: 743 AN XY: 74460

Gnomad4 AFR AF: 0.0376

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00228 Hom.: 3

Bravo AF: 0.0120

ESP6500AA AF: 0.0332 AC: 141

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00323 AC: 391

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MYO9B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Celiac disease, susceptibility to, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.81
DANN	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.57	T;T;T;T
Vest4		0.067
MVP		0.32
MPC		0.84
ClinPred		0.0030	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

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: rs35218876; hg19: chr19-17212694;