rs1942418

Variant names:

• chr18-49856873-C-T
• rs1942418
• NM_001080467.3:c.3962G>A

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.3962G>A​(p.Gly1321Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0723 in 1,613,512 control chromosomes in the GnomAD database, including 9,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1321R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.079 (955 hom., cov: 33)
  • Exomes 𝑓: 0.072 (8270 hom.)
• Consequence: MYO5B NM_001080467.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.59
• Publications: 22 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 (MetaRNN=0.0016974807).
• BP6: Variant 18-49856873-C-T is Benign according to our data. Variant chr18-49856873-C-T is described in ClinVar as Benign. ClinVar VariationId is 327017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO5B	NM_001080467.3	c.3962G>A	p.Gly1321Glu	missense_variant	Exon 30 of 40	ENST00000285039.12	NP_001073936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO5B	ENST00000285039.12	c.3962G>A	p.Gly1321Glu	missense_variant	Exon 30 of 40	1	NM_001080467.3	ENSP00000285039.6

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152190 Hom.: 946 Cov.: 33

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.121 AC: 30124 AN: 249452 AF XY: 0.108

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0933

GnomAD4 exome AF: 0.0715 AC: 104540 AN: 1461204 Hom.: 8270 Cov.: 31 AF XY: 0.0710 AC XY: 51598 AN XY: 726946

African (AFR) AF: 0.0553 AC: 1849 AN: 33460

American (AMR) AF: 0.365 AC: 16339 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 1129 AN: 26134

East Asian (EAS) AF: 0.361 AC: 14315 AN: 39690

South Asian (SAS) AF: 0.103 AC: 8917 AN: 86226

European-Finnish (FIN) AF: 0.0569 AC: 3038 AN: 53406

Middle Eastern (MID) AF: 0.0827 AC: 477 AN: 5766

European-Non Finnish (NFE) AF: 0.0485 AC: 53915 AN: 1111440

Other (OTH) AF: 0.0755 AC: 4561 AN: 60372

GnomAD4 genome AF: 0.0794 AC: 12094 AN: 152308 Hom.: 955 Cov.: 33 AF XY: 0.0840 AC XY: 6257 AN XY: 74464

African (AFR) AF: 0.0547 AC: 2276 AN: 41576

American (AMR) AF: 0.230 AC: 3520 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.296 AC: 1535 AN: 5178

South Asian (SAS) AF: 0.113 AC: 545 AN: 4830

European-Finnish (FIN) AF: 0.0562 AC: 595 AN: 10596

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3251 AN: 68034

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0638 Hom.: 2710

Bravo AF: 0.0957

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.0482 AC: 184

ESP6500EA AF: 0.0517 AC: 427

ExAC AF: 0.109 AC: 13137

Asia WGS AF: 0.177 AC: 613 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0483

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Congenital microvillous atrophy Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.025
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.049	B
Vest4		0.37
MPC		0.71
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.19
gMVP		0.61
Mutation Taster		=54/46	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: rs1942418; hg19: chr18-47383243; COSMIC: COSV53213017;