18-49929610-GAAAAAAA-GAAAAA

Variant names:

• chr18-49929610-GAA-G
• rs56278513
• NM_001080467.3:c.2004-14_2004-13delTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_001080467.3(MYO5B):​c.2004-14_2004-13delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,157,390 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.17 (1 hom.)
• Consequence: MYO5B NM_001080467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.06
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Variant has high frequency in the EAS (0.254) population. However there is too low homozygotes in high coverage region: (expected more than 6850, got 1).
• BP6: Variant 18-49929610-GAA-G is Benign according to our data. Variant chr18-49929610-GAA-G is described in ClinVar as Benign. ClinVar VariationId is 403216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	NM_001080467.3	MANE Select	c.2004-14_2004-13delTT		intron	N/A	NP_001073936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5B	ENST00000285039.12	TSL:1 MANE Select	c.2004-14_2004-13delTT		intron	N/A	ENSP00000285039.6
	MYO5B	ENST00000697219.1		c.1800-14_1800-13delTT		intron	N/A	ENSP00000513188.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 216 AN: 132812 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000875

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00206

Gnomad ASJ AF: 0.00154

Gnomad EAS AF: 0.00152

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00166

GnomAD2 exomes AF: 0.180 AC: 20586 AN: 114366 AF XY: 0.180

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.174 AC: 177873 AN: 1024600 Hom.: 1 AF XY: 0.175 AC XY: 89227 AN XY: 508736

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

African (AFR) AF: 0.169 AC: 3955 AN: 23426

American (AMR) AF: 0.214 AC: 5738 AN: 26808

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 3914 AN: 18656

East Asian (EAS) AF: 0.260 AC: 6626 AN: 25518

South Asian (SAS) AF: 0.184 AC: 11242 AN: 61178

European-Finnish (FIN) AF: 0.173 AC: 5309 AN: 30636

Middle Eastern (MID) AF: 0.207 AC: 625 AN: 3018

European-Non Finnish (NFE) AF: 0.167 AC: 132433 AN: 792740

Other (OTH) AF: 0.188 AC: 8031 AN: 42620

⚠️ 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.

GnomAD4 genome AF: 0.00163 AC: 217 AN: 132790 Hom.: 0 Cov.: 0 AF XY: 0.00197 AC XY: 125 AN XY: 63432

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

African (AFR) AF: 0.000902 AC: 32 AN: 35462

American (AMR) AF: 0.00206 AC: 27 AN: 13136

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 5 AN: 3240

East Asian (EAS) AF: 0.00130 AC: 6 AN: 4602

South Asian (SAS) AF: 0.000246 AC: 1 AN: 4060

European-Finnish (FIN) AF: 0.00640 AC: 44 AN: 6874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00158 AC: 99 AN: 62506

Other (OTH) AF: 0.00165 AC: 3 AN: 1814

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.167 Hom.: 142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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: rs56278513; hg19: chr18-47455980;