18-49877754-A-G

Variant names:

• chr18-49877754-A-G
• rs75971548
• NM_001080467.3:c.3396+9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080467.3(MYO5B):​c.3396+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,613,816 control chromosomes in the GnomAD database, including 3,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (177 hom., cov: 32)
  • Exomes 𝑓: 0.056 (3125 hom.)
• Consequence: MYO5B NM_001080467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0720
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• microvillus inclusion disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• cholestasis, progressive familial intrahepatic, 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial intrahepatic cholestasis type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-49877754-A-G is Benign according to our data. Variant chr18-49877754-A-G is described in ClinVar as Benign. ClinVar VariationId is 327028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO5B	NM_001080467.3	c.3396+9T>C		intron_variant	Intron 25 of 39	ENST00000285039.12	NP_001073936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO5B	ENST00000285039.12	c.3396+9T>C		intron_variant	Intron 25 of 39	1	NM_001080467.3	ENSP00000285039.6

Frequencies

GnomAD3 genomes AF: 0.0422 AC: 6423 AN: 152170 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.00655

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0576 AC: 14368 AN: 249398 AF XY: 0.0644

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0698

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.0606

Gnomad NFE exome AF: 0.0504

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0562 AC: 82162 AN: 1461528 Hom.: 3125 Cov.: 32 AF XY: 0.0600 AC XY: 43630 AN XY: 727072

African (AFR) AF: 0.0219 AC: 734 AN: 33462

American (AMR) AF: 0.0229 AC: 1026 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 1821 AN: 26130

East Asian (EAS) AF: 0.00348 AC: 138 AN: 39686

South Asian (SAS) AF: 0.164 AC: 14184 AN: 86248

European-Finnish (FIN) AF: 0.0617 AC: 3293 AN: 53410

Middle Eastern (MID) AF: 0.0712 AC: 409 AN: 5744

European-Non Finnish (NFE) AF: 0.0514 AC: 57138 AN: 1111764

Other (OTH) AF: 0.0566 AC: 3419 AN: 60366

GnomAD4 genome AF: 0.0422 AC: 6428 AN: 152288 Hom.: 177 Cov.: 32 AF XY: 0.0447 AC XY: 3328 AN XY: 74450

African (AFR) AF: 0.0218 AC: 907 AN: 41566

American (AMR) AF: 0.0271 AC: 415 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.00656 AC: 34 AN: 5182

South Asian (SAS) AF: 0.156 AC: 751 AN: 4820

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3357 AN: 68020

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0483 Hom.: 97

Bravo AF: 0.0370

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.0527

EpiControl AF: 0.0511

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29266534)

Congenital microvillous atrophy Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.38
PhyloP100		0.072
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75971548; hg19: chr18-47404124;