18-49929553-C-T

Position:

• chr18-49929553-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080467.3(MYO5B):​c.2049G>A​(p.Val683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,605,794 control chromosomes in the GnomAD database, including 226,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18337 hom., cov: 26)
  • Exomes 𝑓: 0.53 (208650 hom.)
• Consequence: MYO5B NM_001080467.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.208

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 18-49929553-C-T is Benign according to our data. Variant chr18-49929553-C-T is described in ClinVar as [Benign]. Clinvar id is 327053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-49929553-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.208 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5B	NM_001080467.3	c.2049G>A	p.Val683=	synonymous_variant	17/40	ENST00000285039.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5B	ENST00000285039.12	c.2049G>A	p.Val683=	synonymous_variant	17/40	1	NM_001080467.3	P1
MYO5B	ENST00000697219.1	c.1848G>A	p.Val616=	synonymous_variant	15/38

Frequencies

GnomAD3 genomes AF: 0.486 AC: 72853 AN: 149870 Hom.: 18340 Cov.: 26

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.504

GnomAD3 exomes AF: 0.468 AC: 114072 AN: 243844 Hom.: 28270 AF XY: 0.480 AC XY: 63467 AN XY: 132086

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.472

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.530 AC: 771611 AN: 1455804 Hom.: 208650 Cov.: 50 AF XY: 0.531 AC XY: 384048 AN XY: 723786

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.588

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.559

Gnomad4 OTH exome AF: 0.512

GnomAD4 genome AF: 0.486 AC: 72862 AN: 149990 Hom.: 18337 Cov.: 26 AF XY: 0.481 AC XY: 35166 AN XY: 73064

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.587

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.458

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.500

Alfa AF: 0.535 Hom.: 22710

Bravo AF: 0.473

Asia WGS AF: 0.380 AC: 1324 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital microvillous atrophy Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.6
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2298628; hg19: chr18-47455923; COSMIC: COSV53217506;