rs17659179

chr18-49984743-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080467.3(MYO5B):c.921G>T(p.Lys307Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,612,904 control chromosomes in the GnomAD database, including 2,840 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (192 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2648 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.13

Genes affected

MYO5B (HGNC:7603): (myosin VB) The protein encoded by this gene, together with other proteins, may be involved in plasma membrane recycling. Mutations in this gene are associated with microvillous inclusion disease. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015074998).
• BP6: Variant 18-49984743-C-A is Benign according to our data. Variant chr18-49984743-C-A is described in ClinVar as [Benign]. Clinvar id is 327075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-49984743-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5B	NM_001080467.3	c.921G>T	p.Lys307Asn	missense_variant	8/40	ENST00000285039.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5B	ENST00000285039.12	c.921G>T	p.Lys307Asn	missense_variant	8/40	1	NM_001080467.3	P1
MYO5B	ENST00000697219.1	c.720G>T	p.Lys240Asn	missense_variant	6/38

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7032 AN: 152134 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0450

GnomAD3 exomes AF: 0.0515 AC: 12845 AN: 249500 Hom.: 382 AF XY: 0.0514 AC XY: 6957 AN XY: 135360

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0670

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.00879

Gnomad SAS exome AF: 0.0347

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0576 AC: 84171 AN: 1460652 Hom.: 2648 Cov.: 31 AF XY: 0.0569 AC XY: 41341 AN XY: 726724

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.0636

Gnomad4 ASJ exome AF: 0.0475

Gnomad4 EAS exome AF: 0.00544

Gnomad4 SAS exome AF: 0.0330

Gnomad4 FIN exome AF: 0.0531

Gnomad4 NFE exome AF: 0.0634

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0462 AC: 7031 AN: 152252 Hom.: 192 Cov.: 32 AF XY: 0.0453 AC XY: 3375 AN XY: 74452

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.0532

Gnomad4 ASJ AF: 0.0407

Gnomad4 EAS AF: 0.00928

Gnomad4 SAS AF: 0.0268

Gnomad4 FIN AF: 0.0536

Gnomad4 NFE AF: 0.0635

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0575 Hom.: 530

Bravo AF: 0.0446

ESP6500AA AF: 0.0188 AC: 75

ESP6500EA AF: 0.0577 AC: 482

ExAC AF: 0.0511 AC: 6174

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Congenital microvillous atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 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: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.015	N
MutationTaster	Benign	0.000047	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.32
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.0040	B
Vest4		0.59
MutPred		0.23		Loss of ubiquitination at K307 (P = 0.0297);
MPC		0.69
ClinPred		0.013	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.55

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: rs17659179; hg19: chr18-47511113;