Genetic Variant MYO5B:c.2004-14_2004-13dupTT (chr18-49929610-G-GAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001080467.3(MYO5B):c.2004-14_2004-13dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0094 ( 6 hom., cov: 0)

Exomes 𝑓: 0.0072 ( 7 hom. )

Consequence

MYO5B
NM_001080467.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Publications

2 publications found

Variant links:

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

MYO5B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00945 (1255/132818) while in subpopulation SAS AF = 0.0192 (78/4056). AF 95% confidence interval is 0.0158. There are 6 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO5B	NM_001080467.3 link	c.2004-14_2004-13dupTT		intron_variant	Intron 16 of 39	ENST00000285039.12	NP_001073936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO5B	ENST00000285039.12 link	c.2004-13_2004-12insTT		intron_variant	Intron 16 of 39	1	NM_001080467.3	ENSP00000285039.6
MYO5B	ENST00000697219.1 link	c.1800-13_1800-12insTT		intron_variant	Intron 14 of 37			ENSP00000513188.1

Frequencies

GnomAD3 genomes

AF:

0.00945

AC:

1256

AN:

132840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00305

Gnomad AMI

AF:

0.00476

Gnomad AMR

AF:

0.00480

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.000433

Gnomad SAS

AF:

0.0194

Gnomad FIN

AF:

0.00378

Gnomad MID

AF:

0.0282

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00539

AC:

617

AN:

114366

AF XY:

0.00527

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.000116

Gnomad FIN exome

AF:

0.00159

Gnomad NFE exome

AF:

0.00722

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00718

AC:

8266

AN:

1151292

Hom.:

Cov.:

AF XY:

0.00725

AC XY:

4172

AN XY:

575288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00135

AC:

AN:

26570

American (AMR)

AF:

0.00259

AC:

AN:

31996

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

253

AN:

22040

East Asian (EAS)

AF:

0.00

AC:

AN:

33532

South Asian (SAS)

AF:

0.00896

AC:

626

AN:

69852

European-Finnish (FIN)

AF:

0.00246

AC:

AN:

36110

Middle Eastern (MID)

AF:

0.0129

AC:

AN:

3498

European-Non Finnish (NFE)

AF:

0.00778

AC:

6837

AN:

878878

Other (OTH)

AF:

0.00608

AC:

297

AN:

48816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.332

Heterozygous variant carriers

465

931

1396

1862

2327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00945

AC:

1255

AN:

132818

Hom.:

Cov.:

AF XY:

0.00878

AC XY:

557

AN XY:

63438

show subpopulations

African (AFR)

AF:

0.00305

AC:

108

AN:

35466

American (AMR)

AF:

0.00479

AC:

AN:

13142

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3242

East Asian (EAS)

AF:

0.000434

AC:

AN:

4606

South Asian (SAS)

AF:

0.0192

AC:

AN:

4056

European-Finnish (FIN)

AF:

0.00378

AC:

AN:

6886

Middle Eastern (MID)

AF:

0.0310

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0138

AC:

864

AN:

62508

Other (OTH)

AF:

0.0105

AC:

AN:

1814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00444

Hom.:

142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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18-49929610-GAAAAAAA-GAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over