18-50036929-T-C

Position:

• chr18-50036929-T-C

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.376A>G​(p.Thr126Ala) variant causes a missense change. The variant allele was found at a frequency of 0.996 in 1,614,124 control chromosomes in the GnomAD database, including 800,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72866 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727544 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.18

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]

MYO5B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.517018E-7).
• BP6: Variant 18-50036929-T-C is Benign according to our data. Variant chr18-50036929-T-C is described in ClinVar as [Benign]. Clinvar id is 327087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-50036929-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO5B	NM_001080467.3	c.376A>G	p.Thr126Ala	missense_variant	4/40	ENST00000285039.12	NP_001073936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO5B	ENST00000285039.12	c.376A>G	p.Thr126Ala	missense_variant	4/40	1	NM_001080467.3	ENSP00000285039.6
MYO5B	ENST00000697219.1	c.172A>G	p.Thr58Ala	missense_variant	2/38			ENSP00000513188.1
MYO5B	ENST00000697221.1	n.747A>G		non_coding_transcript_exon_variant	4/5

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148738 AN: 152122 Hom.: 72810 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.983

GnomAD3 exomes AF: 0.994 AC: 248169 AN: 249558 Hom.: 123437 AF XY: 0.996 AC XY: 134827 AN XY: 135394

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.998 AC: 1458388 AN: 1461884 Hom.: 727544 Cov.: 52 AF XY: 0.998 AC XY: 725743 AN XY: 727242

Gnomad4 AFR exome AF: 0.922

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.995

GnomAD4 genome AF: 0.978 AC: 148852 AN: 152240 Hom.: 72866 Cov.: 31 AF XY: 0.979 AC XY: 72837 AN XY: 74428

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.992

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.983

Alfa AF: 0.995 Hom.: 117746

Bravo AF: 0.975

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.931 AC: 3738

ESP6500EA AF: 0.999 AC: 8352

ExAC AF: 0.993 AC: 120012

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital microvillous atrophy Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2019	- -

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.68
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.2	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	2.8	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.14
ClinPred		0.0037	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.13
gMVP		0.33

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: rs1815930; hg19: chr18-47563299;